Compounds and their methods of use

ABSTRACT

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalPatent Application No. 62/545,555, filed on Aug. 15, 2017 and U.S.Provisional Patent Application No. 62/676,615, filed on May 25, 2018,each of which is incorporated herein by reference in its entirety.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and arequickly inactivated, thereby generating a fast Na+ current to initiatethe action potential. The late or persistent sodium current (INaL) is asustained component of the fast Na+ current of cardiac myocytes andneurons. Many common neurological and cardiac conditions are associatedwith abnormal INaL enhancement, which contributes to the pathogenesis ofboth electrical and contractile dysfunction in mammals (see, e.g.,Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceuticalcompounds that selectively modulate sodium channel activity, e.g.,abnormal INaL, are useful in treating such disease states.

SUMMARY OF THE INVENTION

Described herein are fused heteroaryl compounds and compositions usefulfor preventing and/or treating a disease, disorder, or condition, e.g.,a disease, disorder, or condition relating to aberrant function of asodium ion channel, e.g., abnormal late sodium current (INaL). In oneaspect, the present disclosure features compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, the compounds of formula (I) is a compound offormula (I-a):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compounds of formula (I) is a compound offormula (I-b):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compounds of formula (I) is a compound offormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compounds of formula (I) is a compound offormula (I-d):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-e):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, a pharmaceutical composition comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier is provided.

In another aspect, provided herein is a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (I-c),(I-d), or (I-e)). In some embodiments, the method comprisesadministering a disclosed pharmaceutical composition.

In another aspect, provided herein is a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (I-c),(I-d), or (I-e)), or a pharmaceutically acceptable salt thereof or apharmaceutical composition disclosed herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

DETAILED DESCRIPTION OF THE INVENTION

As generally described herein, the present invention provides compoundsand compositions useful for preventing and/or treating a disease,disorder, or condition described herein, e.g., a disease, disorder, orcondition relating to aberrant function of a sodium ion channel, such asabnormal late sodium current (INaL). Exemplary diseases, disorders, orconditions include a neurological disorder (e.g., epilepsy or anepilepsy syndrome, a neurodevelopmental disorder or a neuromusculardisorder), a psychiatric disorder, pain, or a gastrointestinal disorder.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and 3H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and¹⁹F; and the like.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds and pharmaceutically acceptable saltsthereof, pharmaceutical compositions containing such compounds andmethods of using such compounds and compositions, the following terms,if present, have the following meanings unless otherwise indicated. Itshould also be understood that when described herein any of the moietiesdefined forth below may be substituted with a variety of substituents,and that the respective definitions are intended to include suchsubstituted moieties within their scope as set out below. Unlessotherwise stated, the term “substituted” is to be defined as set outbelow. It should be further understood that the terms “groups” and“radicals” can be considered interchangeable when used herein. Thearticles “a” and “an” may be used herein to refer to one or to more thanone (i.e. at least one) of the grammatical objects of the article. Byway of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms(“C₁₋₂₀ alkyl”). In some embodiments, an alkyl group has 1 to 10 carbonatoms (“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl grouphas 1 to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkylgroup has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, analkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments,an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In someembodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). Insome embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”).In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”).Examples of C₁₋₆ alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl, and the like.

As used herein, “alkenyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like.

As used herein, “alkynyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like.

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” or “alkynylene,” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and“alkynylene,” groups may be substituted or unsubstituted with one ormore substituents as described herein.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 t electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has six ring carbon atoms(“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has tenring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has fourteen ring carbonatoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecarbocyclyl or heterocyclyl groups wherein the radical or point ofattachment is on the aryl ring, and in such instances, the number ofcarbon atoms continue to designate the number of carbon atoms in thearyl ring system. Typical aryl groups include, but are not limited to,groups derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, and trinaphthalene. Particularly aryl groups includephenyl, naphthyl, indenyl, and tetrahydronaphthyl.

As used herein, “heteroaryl” refers to a radical of a 5-10 memberedmonocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10electrons shared in a cyclic array) having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthlazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ carbocyclyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbonatoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, withoutlimitation, cyclopropyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈ carbocyclylgroups include, without limitation, the aforementioned C₃₋₆ carbocyclylgroups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl(C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈),bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like.Exemplary C₃₋₁₀ carbocyclyl groups include, without limitation, theaforementioned C₃₋₈ carbocyclyl groups as well as cyclononyl (C₉),cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀),octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical ofa 3- to 10-membered non-aromatic ring system having ring carbon atomsand 1 to 4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon(“3-10 membered heterocyclyl”). In heterocyclyl groups that contain oneor more nitrogen atoms, the point of attachment can be a carbon ornitrogen atom, as valency permits. A heterocyclyl group can either bemonocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ringsystem such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g.,heteroaryl; and the like having from 1 to 5, and particularly from 1 to3 heteroatoms.

As used herein, “cyano” refers to —CN.

As used herein, “halo” or “halogen” refers to fluoro (F), chloro (Cl),bromo (Br) and iodo (I). In certain embodiments, the halo group iseither fluoro or chloro.

As used herein, “haloalkyl” refers to an alkyl group substituted withone or more halogen atoms.

As used herein, “nitro” refers to —NO₂.

As used herein, “oxo” refers to —C═O.

In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, humans (i.e., a male or female of anyage group, e.g., a pediatric subject (e.g, infant, child, adolescent) oradult subject (e.g., young adult, middle-aged adult or senior adult))and/or a non-human animal, e.g., a mammal such as primates (e.g.,cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats,rodents, cats, and/or dogs. In certain embodiments, the subject is ahuman. In certain embodiments, the subject is a non-human animal. Theterms “human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

As used herein, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

Compounds

In one aspect, the present invention features a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, X is CR′ (e.g., CH). In some embodiments, Y is CR′(e.g., CH). In some embodiments, Z is CR′ (e.g., CH). In someembodiments, each of X, Y, and Z is independently CR′ (e.g., CH).

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., —CH₃). In some embodiments, R¹ is C₁₋₆ alkyl substituted with 1-4R⁴. In some embodiments, R¹ is C₁₋₄ alkyl substituted with 1-3 R⁴. Insome embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹ is—CF₃.

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1-2R³. In some embodiments, A is phenyl substituted by 2 R³. In someembodiments, R³ is alkyl or —OR^(c). In some embodiments, R³ is alkyl(—CH₃). In some embodiments, R³ is alkyl substituted with R⁵. In someembodiments, R³ is —CH₂OCH₃. In some embodiments, R³ is —OR^(c). In someembodiments, R^(c) is alkyl. In some embodiments, R^(c) is alkylsubstituted with 1-3 R⁶. In some embodiments, R³ is —OCF₃.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-a):

or a pharmaceutically acceptable salt thereof, wherein

each of X, Y, and Z is independently N or CR′; R′ is hydrogen, alkyl,—OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

n is 0, 1, or 2;

each of R⁴ and R⁵ is independently, alkyl, carbocyclyl, heterocyclyl,halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c),or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, and heterocyclyl isoptionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH; and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, X is CR′ (e.g., CH). In some embodiments, Y is CR′(e.g., CH). In some embodiments, Z is CR′ (e.g., CH). In someembodiments, each of X, Y, and Z is independently CR′ (e.g., CH).

In some embodiments, R¹ is hydrogen, deuterium, or alkyl. In someembodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., —CH₃). In some embodiments, R¹ is C₁₋₆ alkyl substituted with 1-4R⁴. In some embodiments, R¹ is C₁₋₄ alkyl substituted with 1-3 R⁴. Insome embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹ is—CF₃.

In some embodiments, n is 1.

In some embodiments, R^(3a) is alkyl. In some embodiments, R^(3a) isalkyl (—CH₃). In some embodiments, R^(3a) is alkyl substituted with R⁵.In some embodiments, R^(3a) is —CH₂OCH₃.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-b):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, aryl, orheteroaryl, wherein alkyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo,

cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, R¹ is hydrogen, deuterium, or alkyl. In someembodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., —CH₃). In some embodiments, R¹ is C₁₋₆ alkyl substituted with 1-4R⁴. In some embodiments, R¹ is C₁₋₄ alkyl substituted with 1-3 R⁴. Insome embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹ is—CF₃.

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1-2R³. In some embodiments, A is phenyl substituted by 2 R³. In someembodiments, R³ is alkyl or —OR^(c). In some embodiments, R³ is alkyl(—CH₃). In some embodiments, R³ is alkyl substituted with R⁵. In someembodiments, R³ is —CH₂OCH₃. In some embodiments, R³ is —OR^(c). In someembodiments, R^(c) is alkyl. In some embodiments, R^(c) is alkylsubstituted with 1-3 R⁶. In some embodiments, R³ is —OCF₃.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

n is 0, 1, or 2;

R^(3b) is alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, carbocyclyl, heterocyclyl,halo, cyano,

nitro, or —OH; and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-d):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

-   -   m is 1, 2, or 3;    -   each of R⁴ and R⁵ is independently, alkyl, carbocyclyl,        heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂,        —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl,        carbocyclyl, and heterocyclyl is optionally substituted by one        or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-e):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

-   -   p is 0, 1, 2, or 3;    -   each of R⁴ and R⁵ is independently, alkyl, deuterium,        carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c),        —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein        alkyl, carbocyclyl, and heterocyclyl is optionally substituted        by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, carbocyclyl, heterocyclyl,halo, cyano,

nitro, or —OH; and each R⁷ is independently alkyl, halo, or oxo.

In some embodiments of formula (I-c), (I-d), or (I-e), X, Y, and Z areCR′.

In some embodiments of formula (I-c), (I-d), or (I-e), X is N, Y and Zare CR′.

In some embodiments of formula (I-c), (I-d), or (I-e), Y is N, X and Zare CR′.

In some embodiments of formula (I-c), (L-d), or (I-e), Z is N, X and Yare CR′.

In some embodiments of formula (I-c), (I-d), or (I-e), R′ is hydrogen.

In some embodiments of formula (I-c), (I-d), or (I-e), R′ is methyl.

In some embodiments of formula (I-c), (I-d), or (I-e), R¹ is hydrogen,deuterium, or alkyl, wherein the alkyl is optionally substituted withone or more (e.g., 1, 2, or 3) R⁴.

In some embodiments of formula (I-c), (I-d), or (I-e), R¹ is hydrogen oralkyl, wherein the alkyl is optionally substituted with one or more(e.g., 1, 2, or 3) R⁴.

In some embodiments of formula (I-c), (I-d), or (I-e), each R^(3a) isindependently, alkyl, carbocyclyl, halo, or —OR^(c), wherein the alkyland carbocyclyl are optionally substituted with one or more R⁵.

In some embodiments of formula (I-c), (I-d), or (I-e), n is 0 or 1.

In some embodiments of formula (I-c), (I-d), or (I-e), m is 1 or 2.

In some embodiments of formula (I-c), (I-d), or (I-e), R^(3b) is alkylor carbocyclyl, wherein alkyl and carbocyclyl are optionally substitutedwith one or more R⁵.

In some embodiments of formula (I-c), (I-d), or (I-e), each of R⁴ isindependently halo or —OR^(c).

In some embodiments of formula (I-c), (I-d), or (I-e), each of R⁵ isindependently, alkyl, halo, cyano, or —OR^(c), wherein alkyl isoptionally substituted by one or more R⁷.

In some embodiments of formula (I-c), (I-d), or (I-e), each R^(c) isindependently alkyl, wherein alkyl is optionally substituted by one ormore R⁶.

In some embodiments of formula (I-c), (I-d), or (I-e), each R⁶ isindependently halo.

In some embodiments of formula (I-c), (I-d), or (I-e), each R⁷ isindependently halo.

In any and all aspects, in some embodiments, the compound of Formulas(I), (I-a), (I-b), (I-c), (I-d), or (I-e) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

Methods of Treatment

Described herein are compounds and compositions thereof and their use totreat a disease, disorder, or condition relating to aberrant function ofa sodium channel ion channel, e.g., abnormal late sodium (INaL) current.In some embodiments, a compound provided by the present invention iseffective in the treatment of epilepsy or an epilepsy syndrome, aneurodevelopmental disorder, pain, or a neuromuscular disorder.Compounds of the invention may also modulate all sodium ion channels ormay be specific to only one or a plurality of sodium ion channels, e.g.,Nay 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and/or 1.9.

In typical embodiments, the present invention is intended to encompassthe compounds disclosed herein, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, tautomeric forms, polymorphs,and prodrugs of such compounds. In some embodiments, the presentinvention includes a pharmaceutically acceptable addition salt, apharmaceutically acceptable ester, a solvate (e.g., hydrate) of anaddition salt, a tautomeric form, a polymorph, an enantiomer, a mixtureof enantiomers, a stereoisomer or mixture of stereoisomers (pure or as aracemic or non-racemic mixture) of a compound described herein, e.g. acompound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e); such as acompound of Formula named herein.

Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsyand epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cellactivity in the brain becomes disrupted, causing seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness.Seizure symptoms will vary widely, from a simple blank stare for a fewseconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focalseizure. All areas of the brain are involved in a generalized seizure. Aperson experiencing a generalized seizure may cry out or make somesound, stiffen for several seconds to a minute a then have rhythmicmovements of the arms and legs. The eyes are generally open, the personmay appear not to be breathing and may actually turn blue. The return toconsciousness is gradual and the person maybe confused from minutes tohours. There are six main types of generalized seizures: tonic-clonic,tonic, clonic, myoclonic, absence, and atonic seizures. In a partial orfocal seizure, only part of the brain is involved, so only part of thebody is affected. Depending on the part of the brain having abnormalelectrical activity, symptoms may vary.

Epilepsy, as described herein, includes a generalized, partial, complexpartial, tonic clonic, clonic, tonic, refractory seizures, statusepilepticus, absence seizures, febrile seizures, or temporal lobeepilepsy.

The compounds described herein may also be useful in the treatment ofepilepsy syndromes. Severe syndromes with diffuse brain dysfunctioncaused, at least partly, by some aspect of epilepsy, are also referredto as epileptic encephalopathies. These are associated with frequentseizures that are resistant to treatment and severe cognitivedysfunction, for instance West syndrome.

In some embodiments, the epilepsy syndrome comprises an epilepticencephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5disorder, frontal lobe epilepsy, infantile spasms, West's syndrome,Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastautsyndrome, Ohtahara syndrome, PCDH19 epilepsy, or Gluti deficiency.

In some embodiments, the epilepsy or epilepsy syndrome is a geneticepilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsyor an epilepsy syndrome comprises epileptic encephalopathy, epilepticencephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantileepileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1Amutation, generalized epilepsy with febrile seizures, intractablechildhood epilepsy with generalized tonic-clonic seizures, infantilespasms, benign familial neonatal-infantile seizures, SCN2A epilepticencephalopathy, focal epilepsy with SCN3A mutation, cryptogenicpediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy.

In some embodiments, the methods described herein further compriseidentifying a subject having epilepsy or an epilepsy syndrome (e.g.,epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden unexpected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, or KCNT1 epileptic encephalopathy) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-a), (I-b), (I-c), (I-d), or (I-e)).

In one aspect, the present invention features a method of treatingepilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy,epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, earlyinfantile epileptic encephalopathy, Dravet syndrome, Dravet syndromewith SCN1A mutation, generalized Epilepsy with febrile seizures,intractable childhood epilepsy with generalized tonic-clonic seizures,infantile spasms, benign familial neonatal-infantile seizures, SCN2Aepileptic encephalopathy, focal epilepsy with SCN3A mutation,cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8Aepileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy) comprising administering to a subject in need thereof acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c) or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

A compound of the present invention (e.g., a compound of Formula (I))may also be used to treat an epileptic encephalopathy, wherein thesubject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX,ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB,DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1,GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1,KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1,PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B,SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2,SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1,SYNGAP1, SZT2, TBCID24, and WWOX.

In some embodiments, the methods described herein further compriseidentifying a subject having a mutation in one or more of ALDH7A1,ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8,CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEFIA2, EPM2A, EPM2B, GABRA1, GABRB3,GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2,KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1,PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2,SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22,SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B,STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administrationof a compound described herein (e.g., a compound of Formula (I), (I-a),(I-b), (I-c), (I-d), or (I-e)).

Neurodevelopmental Disorders

The compounds described herein may be useful in the treatment of aneurodevelopmental disorder. In some embodiments, the neurodevelopmentaldisorder comprises autism, autism with epilepsy, tuberous sclerosis,Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome,22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacialsyndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorderwith epilepsy. In some embodiments, the methods described herein furthercomprise identifying a subject having a neurodevelopmental disorder(e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile Xsyndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder withepilepsy) prior to administration of a compound described herein (e.g.,a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e)).

In one aspect, the present invention features a method of treating aneurodevelopmental disorder (e.g., autism, autism with epilepsy,tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelmansyndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willisyndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy) comprising administering to asubject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c) or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

Pain

The compounds described herein may be useful in the treatment of pain.In some embodiments, the pain comprises neuropathic pain, trigeminalneuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine,familial hemiplegic migraine type 3, cluster headache, trigeminalneuralgia, cerebellar ataxia, or a related headache disorder. In someembodiments, the methods described herein further comprise identifying asubject having pain (e.g., neuropathic pain, trigeminal neuralgia,migraine, hemiplegic migraine, familial hemiplegic migraine, familialhemiplegic migraine type 3, cluster headache, trigeminal neuralgia,cerebellar ataxia, or a related headache disorder) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-a), (I-b), (I-c), (I-d), or (I-e)).

In one aspect, the present invention features a method of treating pain(e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegicmigraine, familial hemiplegic migraine, familial hemiplegic migrainetype 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or arelated headache disorder) comprising administering to a subject in needthereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c) or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

Neuromuscular Disorders

The compounds described herein may be useful in the treatment of aneuromuscular disorder. In some embodiments, the neuromuscular disordercomprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia,paramyotonia congenita, potassium-aggravated myotonia, periodicparalysis, hyperkalemic periodic paralysis, hypokalemic periodicparalysis, or laryngospasm with SCN4A mutation. In some embodiments, themethods described herein further comprise identifying a subject having aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)prior to administration of a compound described herein (e.g., a compoundof Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e)).

In one aspect, the present invention features a method of treating aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)comprising administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c) or halogen;

R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl, whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently, alkyl, deuterium, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷;

each R is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

Other Disorders

In some embodiments, a compound of the present invention (e.g., acompound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e)) may haveappropriate pharmacokinetic properties such that they may be active withregard to the central and/or peripheral nervous system. In someembodiments, the compounds provided herein are used to treat acardiovascular disease such as atrial and ventricular arrhythmias,including atrial fibrillation, Prinzmetal's (variant) angina, stableangina, unstable angina, ischemia and reperfusion injury in cardiac,kidney, liver and the brain, exercise induced angina, pulmonaryhypertension, congestive heart disease including diastolic and systolicheart failure, and myocardial infarction. In some embodiments, thecompounds provided herein may be used in the treatment of diseasesaffecting the neuromuscular system resulting in itching, seizures, orparalysis, or in the treatment of diabetes or reduced insulinsensitivity, and disease states related to diabetes, such as diabeticperipheral neuropathy.

In some embodiments, a disclosed method comprises administering thepharmaceutical composition.

In some embodiments, provided herein is a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein, or a pharmaceutically acceptable salt thereof or apharmaceutical composition disclosed herein.

In any and all aspects, in some embodiments, the compound of Formula(I), (I-a), (I-b), (I-c), (I-d), or (I-e) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usuallyadministered in the form of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

In some embodiments, a pharmaceutical composition comprising a disclosedcompound, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Combination Therapy

A compound or composition described herein (e.g., for use in modulatinga sodium ion channel, e.g., the late sodium (INaL) current) may beadministered in combination with another agent or therapy. A subject tobe administered a compound disclosed herein may have a disease,disorder, or condition, or a symptom thereof, that would benefit fromtreatment with another agent or therapy. These diseases or conditionscan relate to epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder.

Antiepilepsy Agents

Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam,clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide,ezogabine, felbamate, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital,phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate,valproic acid, vigabatrin, zonisamide, and cannabidiol.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the sodium channel blockers of the inventionwith other therapeutic agents include, without limitation, anginaincluding stable angina, unstable angina (UA), exercised-induced angina,variant angina, arrhythmias, intermittent claudication, myocardialinfarction including non-STE myocardial infarction (NSTEMI), pulmonaryhypertension including pulmonary arterial hypertension, heart failureincluding congestive (or chronic) heart failure and diastolic heartfailure and heart failure with preserved ejection fraction (diastolicdysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the sodium channel blockers of the inventionwith therapeutic agents suitable for treating cardiovascular relatedconditions allows enhancement in the standard of care therapy thepatient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral),atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide(Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc),labetalol (Normodyne, Trandatc), metoprolol (Lupressor, Toprol XL),nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), andtimolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc, Lotrel),bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil),nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine(Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents Agents used to treat heart failure includediuretics, ACE inhibitors, vasodilators, and cardiac glycosides.Diuretics eliminate excess fluids in the tissues and circulation therebyrelieving many of the symptoms of heart failure. Examples of diureticsinclude hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix),bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin),captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril),lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril(Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril(Mavik).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(plavix), dipyridamole, cilostazol, persantine sulfinpyrazone,dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, suchas abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockersand calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax), warfarin (Coumadin), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interestgiven the recently discovered synergistic effects of the sodium channelblocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot forillation. Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura),prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide),and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, suchas propranolol (Inderal), nadolol (Corgard), timolol (Blocadren),metoprolol (Lopressor), and pindolol (Visken); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres),clonidine hydrochloride and chlorthalidone (Clorpres, Combipres),guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex),methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor),methyldopa and hydrochlorothiazide (Aldoril); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne,Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, suchas guanethidine (ismelin), reserpine (Serpasil); central nervoussystem-acting antihypertensives, such as clonidine (Catapres),methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents;ACE inhibitors, such as perindopril (Aceon) captopril (Capoten),enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-IIreceptor antagonists, such as Candesartan (Atacand), Eprosartan(Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan(Micardis), Valsartan (Diovan); calcium channel blockers, such asverapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat,Procardia); diuretics; direct vasodilators, such as nitroprusside(Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil(Loniten), verapamil; and potassium channel activators, such asaprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip), ciprofibratc (Modalim), and statins, suchas atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor,Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin(Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary diseaseevent often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient ranolazine in combination with at least one therapeuticagent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil),salmeterol (Serevent, Serevent Diskus), theophylline, ipratropiumbromide (Atrovent), tiotropium (Spiriva), methylprednisolone(Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix),lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec),rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine(Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, suchas misoprostoL (Cytotec); sucralfate; and antacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with ranolazine.

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include .beta.-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor),cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid),cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax),cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, andmonobactams; tetracyclines, such as tetracycline; macrolide antibiotics,such as erythromycin; aminoglycosides, such as gentamicin, tobramycin,amikacin; quinolones such as ciprofloxacin; cyclic peptides, such asvancomycin, strcptogramins, polymyxins; lincosamides, such asclindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics,such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the sodium channel blockers of the invention to treatneuropathic pain via inhibition of the Na_(V) 1.7 and 1.8 sodiumchannels, combination with analgesics are particularly envisioned. SeeU.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillizers. Examples of antidepressant and anti-anxiety agentsinclude benzodiazepines, such as diazepam, lorazepam, and midazolam;benzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem,Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine(Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine(Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane);paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline(Elavil); and bupropion (Wellbutrin, Zyban).

Accordingly, one aspect of the invention provides for a compositioncomprising the sodium channel blockers of the invention and at least onetherapeutic agent. In an alternative embodiment, the compositioncomprises the sodium channel blockers of the invention and at least twotherapeutic agents. In further alternative embodiments, the compositioncomprises the sodium channel blockers of the invention and at leastthree therapeutic agents, the sodium channel blockers of the inventionand at least four therapeutic agents, or the sodium channel blockers ofthe invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the sodium channel blockers of the invention andtherapeutic agent or agents, essentially contemporaneous administrationof more than one formulation comprising the sodium channel blocker ofthe invention and therapeutic agent or agents, and consecutiveadministration of a sodium channel blocker of the invention andtherapeutic agent or agents, in any order, wherein preferably there is atime period where the sodium channel blocker of the invention andtherapeutic agent or agents simultaneously exert their therapeuticeffect.

Examples

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimal reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include recrystallization,filtration, flash chromatography, trituration, high pressure liquidchromatography (HPLC), or supercritical fluid chromatography (SFC). Notethat flash chromatography may either be performed manually or via anautomated system. The compounds provided herein may be characterized byknown standard procedures, such as nuclear magnetic resonancespectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS).NMR chemical shifts are reported in part per million (ppm) and aregenerated using methods well known to those of skill in the art.

Exemplary general methods for analytical LCMS include Method A (XtimateC₁₈ (2.1 mm×30 mm, 3 rtm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA);50° C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6minutes) and Method B (Chromolith Flash RP-18 endcapped C₁₈ (2 mm×25mm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA); 50° C.; 1.5 mL/min;5-95% B over 0.7 minutes, then 95% B for 0.4 minutes).

List of Abbreviations

Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichlorideTEA triethylamineMeI methyliodideNaH sodium hydrideTHF tetrahydrofuranTsNHNH₂ p-Toluenesulfonyl hydrazidePd(t-Bu₃P)₂ bis(tri-tert-butylphosphine)palladium(0)TMSCl trimethylsilyl chloride

DMF N,N-dimethylformamide

n-BuLi n-butyllithiumAgOTf silver trifluoromethanesulfonateMeOH methanolDCM dichloromethaneEtOH ethanolAcN acetonitrilePPh₃ triphenylphosphineDEAD diethyl azodicarboxylateTBAF tetrabutylammonium fluorideTMEDA tetramethylethylenediaminep-ABSA 4-acetamidobenzenesulfonyl azideDBU 1,8-diazabicyclo(5.4.0)undec-7-eneDIBAL-H diisobutylaluminium hydrideDAST diethylaminosulfur trifluoride

Example 1. Synthesis of Compound 1

Synthesis of A-2

A mixture of A-1 (1.5 g, 10.6 mmol) and 4-methylbenzenesulfonohydrazide(1.97 g, 10.6 mmol) in methanol (15 mL) was stirred at 20° C. for 3hours. The solid was collected by filtration, washed with MeOH (3 mL),and dried in oven to afford A-2 (2400 mg, 7.75 mmol) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=11.96 (s, 1H), 8.53 (d, 1H), 7.90 (s, 1H), 7.78(d, 2H), 7.71 (d, 1H), 7.53 (dd, 1H), 7.43 (d, 2H), 2.37 (s, 3H).

Synthesis of A-3

A mixture of A-2 (2.2 g, 7.1 mmol) in morpholine (12 mL, 137.81 mmol)was stirred at 100° C. for 1 hour. After cooling to room temperature,the mixture was concentrated to a residue that was diluted with H₂O (30mL) and extracted with EtOAc (100 mL×2). The combined organic phase waswashed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby flash chromatography on silica gel (EtOAc in PE=10% to 20% to 30%) toafford A-3 (950 mg, 6.08 mmol) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H)=8.68 (d, 1H), 8.02 (d, 1H), 7.74 (d, 1H),6.96 (dd, 1H). LCMS R_(t)=0.480 min using Method B, MS ESI calcd. forC₆H₅ClN₃ [M+H]⁺ 154.0, found 153.8.

Synthesis of Compound 1

A mixture of A-3 (70 mg, 0.46 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(206.55 mg, 0.68 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (55.84 mg, 0.07 mmol) andCs₂CO₃ (297.01 mg, 0.91 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasstirred at 85° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was concentrated to the residue. The residuewas diluted with H₂O (20 mL), and the mixture was extracted with EtOAc(30 mL×2). The combined organic phase was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give acrude product that was purified by prep-TLC (silica gel, PE/EtOAc=3/1)to afford Compound 1 (67.45 mg, 0.23 mmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.79 (d, 1H), 8.11 (d, 1H), 7.64 (s, 1H), 7.30 (d, 1H),7.21-7.13 (m, 2H), 6.96 (dd, 1H), 2.34 (s, 3H). LCMS R_(t)=1.180 minusing Method A, MS ESI calcd. for C₁₄H₁₁F₃N₃O [M+H]⁺ 294.1, found 293.9.

Example 2. Synthesis of Compound 2

A mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (5.00 g, 18.15mmol), Pd(dppf)Cl₂.CH₂Cl₂ (1.48 g, 1.82 mmol) and Et₃N (7.55 mL, 54.45mmol) in EtOH (30.00 mL) was degassed, and refilled with CO. Thereaction was stirred under CO (50 psi) for 16 hours at 80° C. Thereaction mixture was diluted with EtOH (20 mL), filtered through Celite,concentrated, and purified by flash chromatography on silica gel (EtOAcin PE=0%-5%) to afford A-3b (2.40 g, 8.93 mmol) as an oil. ¹H NMR (400MHz, CDCl₃) δ_(H)=7.66-7.59 (m, 1H), 7.42 (d, 1H), 7.24-7.19 (m, 1H),4.36 (q, 2H), 1.35 (t, 3H).

To a solution of A-3b (2.40 g, 8.93 mmol) in THF (30 mL) at −40° C. wasadded LiAlH₄ (406.67 mg, 10.72 mmol) slowly. The reaction was stirred at−40° C. for 1 hour. The reaction was quenched with sat. NH₄Cl (0.4 mL),diluted with EtOAc (30 mL), and the solid formed was filtered throughCelite and eluted with EtOAc (30 mL). The filtrate was concentrated andpurified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to20%) to afford A-3c (1.50 g, 6.62 mmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=7.45-7.42 (m, 1H), 7.38 (d, 1H), 7.13-7.08 (m, 1H), 4.80(d, 2H), 2.04 (t, 1H).

To a solution of A-3c (1.50 g, 6.62 mmol, 1.00 eq) in THF (20 mL) at 0°C. was added NaH (317.76 mg, 7.94 mmol, 60% purity) slowly. The mixturewas stirred at 0° C. for 30 min, then MeI (1.24 mL, 19.86 mmol) wasadded, and the reaction was stirred at 20° C. for 16 hours. The reactionmixture was quenched with sat. NH₄Cl (50 mL), extracted with EtOAc (50mL×3). The combined organic phase was washed with brine (50 mL), driedover Na₂SO₄, filtered, and concentrated, and the residue was purified byflash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) toafford A-3d (1.40 g, 5.82 mmol) as an oil. ¹H NMR (400 MHz CDCl₃)δ_(H)=7.43-7.32 (m, 2H), 7.09 (dd, 1H), 4.54 (s, 2H), 3.50 (s, 3H).

A mixture of A-3d (400.00 mg, 1.66 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(505.85 mg, 1.99 mmol), KOAc (325.82 mg, 3.32 mmol), X-Phos (197.84 mg,415.00 μmol) and Pd₂(dba)₃ (152.01 mg, 166.00 μmol) in dioxane (6 mL)was stirred under N₂ at 80° C. for 16 hours. The mixture was cooled toroom temperature, concentrated, and the residue was purified by flashchromatography on silica gel (PE:EtOAc=1:0 to 50:1) to afford A-3e(300.00 mg, 903.29 μmol) as an oil. LCMS R_(t)=0.99 min using Method B,MS ESI calcd. for C₁₅H₂₁BF₃O₄ [M+H]+ 333.1, found 332.7.

A mixture of A-3 (70 mg, 0.46 mmol),2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(250 mg, 0.75 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (55.84 mg, 0.07 mmol) and Cs₂CO₃(297.01 mg, 0.91 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasstirred at 85° C. for 12 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (20 mL) and extracted withEtOAc (30 mL×2). The combined organic phase was washed with water (20mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified by prep-TLC (silica gel,PE/EtOAc=3/1) to afford Compound 2 (11.25 mg, 0.034 mmol) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H).=8.79 (d, 1H), 8.13 (s, 1H), 7.73 (s, 1H),7.45 (s, 1H), 7.38 (d, 1H), 7.37-7.27 (m, 1H), 7.05 (dd, 1H), 4.33 (s,2H), 3.39 (s, 3H). LCMS R_(t)=1.141 min using Method B, MS ESI calcd.for C₁₅H₁₃F₃N₃O₂[M+H]⁺ 324.1, found 323.9.

Example 3. Synthesis of Compound 3

Synthesis of A-5

To a mixture of A-4 (3 g, 21.65 mmol) in THF (60 mL) was addedbromo(methyl)magnesium (14.44 mL, 43.31 mmol) at 0° C., then the mixturewas stirred at 0° C. for 2 hours. The reaction mixture was added toice-water (50 mL) and 2 M HCl (25 mL), stirred for 15 minutes, andextracted with EtOAc (50 mL×2). The combined organic phase was washedwith water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to affordA-5 (660 mg, 3.31 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.59(d, 1H), 8.04 (d, 1H), 7.48 (dd, 1H), 2.73 (s, 3H). LCMS Rt=0.640 minusing Method B, MS ESI calcd. for C₇H₇ClNO [M+H]⁺ 156.0, found 155.8.

Synthesis of A-6

A mixture A-5 (600 mg, 3.01 mmol) and 4-methylbenzenesulfonohydrazide(840.41 mg, 4.51 mmol) in ethanol (10 mL) was stirred at 20° C. for 2hours. The solid was collected by filtration, washed with PE (3 mL), anddried to afford A-6 (940 mg, 2.84 mmol) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ_(H)=10.97 (s, 1H), 8.54 (d, 1H), 7.82 (d, 2H), 7.71 (d, 1H),7.54 (dd, 1H), 7.43 (d, 2H), 2.38 (s, 3H), 2.24 (s, 3H). LCMS Rt=0.807min using Method A, MS ESI calcd. for C₁₄H₁₅ClN₃O₂S [M+H]⁺ 324.0, found323.9.

Synthesis of A-7

A mixture of A-6 (940 mg, 2.9 mmol) in morpholine (10 mL, 114.78 mmol)was stirred at 100° C. for 1 hour. After cooling to room temperature,the mixture was concentrated to a residue that was diluted with H₂O (30mL) and extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0% to 25% to 50%) to affordA-7 (440 mg, 2.60 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.58(d, 1H), 7.62 (d, 1H), 6.89 (dd, 1H), 2.60 (s, 3H). LCMS R_(t)=0.638 minusing Method B, MS ESI calcd. for C₇H₇ClN₃ [M+H]⁺ 168.0, found 167.8.

Synthesis of Compound 3

A mixture of A-7 (120 mg, 0.72 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(302.82 mg, 1 mmol), Pd(t-Bu₃P)₂ (54.89 mg, 0.11 mmol) and K₃PO₄ (304.01mg, 1.43 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80°C. for 5 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (20 mL) and extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with water (20 mL) and brine (20 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified by prep-TLC (silica gel, PE/EtOAc=2/1) to affordCompound 3 (142.3 mg, 0.463 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.69 (d, 1H), 7.51 (s, 1H), 7.30 (d, 1H), 7.21-7.13 (m, 2H), 6.90(dd, 1H), 2.65 (s, 3H), 2.34 (s, 3H). LCMS Rt=1.231 min using Method A,MS ESI calcd. for C₁₅H₁₃F₃N₃O [M+H]⁺ 308.1, found 307.9.

Example 4. Synthesis of Compound 4

Synthesis of A-8

To a mixture of Compound 1 (500 mg, 1.71 mmol) in THF (10 mL) was addedn-BuLi (2.05 mL, 5.12 mmol) at −78° C. under N₂, then the mixture wasstirred at −78° C. for 2 hours. To the mixture was addedchloro(trimethyl)silane (370.48 mg, 3.41 mmol), then the mixture wasstirred at −78° C. to 20° C. for 2 hours. The mixture was quenched withsat. NH₄Cl (20 mL) and extracted with EtOAc (30 mL×2). The combinedorganic phase was washed with brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to affordA-8 (340 mg, 0.85 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.10(s, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 7.21-7.13 (m, 2H), 6.97 (d, 1H),2.33 (s, 3H), 0.54 (s, 9H). LCMS Rt=0.985 min using Method B, MS ESIcalcd. for C₁₇H₁₉F₃N₃OSi [M+H]⁺ 366.1, found 366.0.

Synthesis of A-9

To a mixture of A-8 (320 mg, 0.88 mmol) in THF (10 mL) was added n-BuLi(1.4 mL, 3.5 mmol) at −78° C. under N₂, and then the mixture was stirredat −78° C. for 2 hours. To the mixture was added I₂ (444.51 mg, 1.75mmol), then the mixture was stirred at −78° C. to 20° C. for 2 hours.The mixture was quenched with sat. NH₄Cl (20 mL), and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith sat. Na₂S₂O₃ (20 mL) and brine (30 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10%) to afford A-9 (230mg, 0.38 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.47 (d, 1H),7.31 (d, 1H), 7.21-7.15 (m, 2H), 7.01 (d, 1H), 2.34 (s, 3H), 0.53 (s,9H).

Synthesis of Compound 4

A mixture of A-9 (150 mg, 0.31 mmol) and A-10 (381.94 mg, 1.22 mmol) inDMF (2 mL) was stirred at 45° C. for 24 hours in 10 mL sealed tube underN₂. After cooling to room temperature, the mixture was diluted with H₂O(10 mL) and extracted with EtOAc (20 mL×2). The combined organic phasewas washed with water (10 mL×2) and brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby prep-TLC (silica gel, PE/EtOAc=4/1) to afford Compound 4 (21.69 mg,0.06 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.86 (dd, 1H), 7.77(s, 1H), 7.32 (d, 1H), 7.24-7.17 (m, 2H), 7.12 (dd, 1H), 2.35 (s, 3H).LCMS R_(t)=1.336 min using Method A, MS ESI calcd. for C₁₅H₁₀F₆N₃O[M+H]⁺ 362.1, found 362.0.

Example 5. Synthesis of Compound 5

To a mixture of5-[2-methyl-4-(trifluoromethoxy)phenyl]triazolo[1,5-a]pyridine (100 mg,0.34 mmol) in THF (4 mL) was added n-BuLi (0.41 mL, 1.02 mmol) at −78°C. under N₂, then the mixture was stirred at −78° C. for 2 hours. To themixture was added iodomethane (145.21 mg, 1.02 mmol), then the mixturewas allowed to warm to 20° C. slowly and stirred at for 2 hours. Themixture was quenched with sat. NH₄Cl (10 mL), then the mixture wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-TLC(PE:EtOAc=4:1) to give the product (10.76 mg, 0.035 mmol, 10% yield)) asa solid. ¹H NMR (400 MHz, DMSO-d₆) 5=8.27 (s, 1H), 7.85 (s, 1H), 7.45(d, 1H), 7.39 (s, 1H), 7.31 (d, 1H), 7.14 (s, 1H), 2.85 (s, 3H), 2.33(s, 3H). LCMS Rt=1.233 min in 2.0 min chromatography, 10-80AB, purity100%, MS ESI calcd. for C₁₅H₁₃F₃N₃O [M+H]⁺ 308.1, found 307.9.

Example 6. Synthesis of Compound 6

A mixture of 5-chloro-3-methyl-triazolo[1,5-a]pyridine (50 mg, 0.30mmol),1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile(102.1 mg, 0.36 mmol), Pd(t-Bu₃P)₂ (22.87 mg, 0.04 mmol) and K₃PO₄(126.67 mg, 0.60 mmol) in 1,4-Dioxane (2 mL) and Water (0.2 mL) wasstirred at 80° C. for 16 hours to give a brown mixture. After cooling toroom temperature, the suspension was diluted with EtOAc (10 mL),filtered through Celite and eluted with EtOAc (20 mL). And the combinedfiltrates were concentrated to give crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=20% to 70%)to give the product (32.6 mg, 0.11 mmol, 38% yield) as a solid. ¹H NMR(400 MHZ, DMSO-d₆) δ_(H)=9.02 (d, 1H), 8.25 (s, 1H), 7.90 (d, 2H),7.51-7.44 (m, 3H), 2.59 (s, 3H), 1.84-1.79 (m, 2H), 1.61-1.56 (m, 2H).LCMS R_(t)=1.02 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₁₇H₁₅N₄ [M+H]⁺ 275.1, found 274.9.

Example 7. Synthesis of Compound 7

A mixture of 5-chloro-3-methyl-triazolo[1,5-a]pyridine (70 mg, 0.42mmol), [4-(trifluoromethoxy)phenyl]boronic acid (103.21 mg, 0.50 mmol),Pd(t-Bu₃P)₂ (32.02 mg, 0.06 mmol) and K₃PO₄ (177.34 mg, 0.84 mmol) in1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 80° C. for 5 hoursunder N₂. After cooling to room temperature, the mixture was dilutedwith H₂O (20 mL), and the mixture was extracted with EtOAc (30 mL×2).The combined organic phase was washed with water (20 mL) and brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=3:1) to give the product (28.61 mg, 0.10 mmol, 23% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.72 (d, 1H), 7.75 (s, 1H), 7.68(d, 2H), 7.36 (d, 2H), 7.17 (dd, 1H), 2.68 (s, 3H). LCMS R_(t)=1.17 minin 2.0 min chromatography, 10-80AB, purity 100.00%, MS ESI calcd. forC₁₄H₁₁F₃N₃O [M+H]⁺ 294.1, found 293.9.

Example 8. Synthesis of Compound 8

A mixture of 5-chloro-3-methyl-triazolo[1,5-a]pyridine (50 mg, 0.30mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(114.95 mg, 0.36 mmol), Pd(t-Bu₃P)₂ (22.87 mg, 0.04 mmol) and K₃PO₄(126.67 mg, 0.60 mmol) in Water (0.2 mL) and 1,4-Dioxane (2 mL) wasstirred at 80° C. for 16 hours to give a brown mixture. After cooling toroom temperature, the suspension was diluted with EtOAc (10 mL),filtered through silica gel, eluted with EtOAc (20 mL). The combinedfiltrates were concentrated to afford the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=20% to 70%) to give the impure product. The impure product was thenpurified by Prep-TLC (silica gel, PE:EtOAc=1:2) to give the product(28.27 mg, 0.09 mmol, 29% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.74 (d, 1H), 8.24 (d, 1H), 7.75-7.68 (m, 2H), 7.11 (dd, 1H), 4.92(q, 2H), 2.68 (s, 3H). LCMS R_(t)=1.08 min in 2.0 min chromatography,10-80AB, purity 100%, MS ESI calcd. for C₁₄H₁₁F₄N₄O [M+H]⁺ 327.1, found326.9.

Example 9. Synthesis of Compound 9

A mixture of 5-chlorotriazolo[1,5-a]pyridine (70 mg, 0.46 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (112.64 mg, 0.55 mmol),Pd(t-Bu₃P)₂ (23.29 mg, 0.05 mmol) and K₃PO₄ (193.54 mg, 0.91 mmol) in1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 80° C. for 16 hoursunder N₂. After cooling to room temperature, the mixture was dilutedwith H₂O (20 mL), and the mixture was extracted with EtOAc (40 mL×2).The combined organic phase was washed with water (20 mL) and brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=3:1) to give the product (7.82 mg, 0.03 mmol, 6% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.82 (d, 1H), 8.14 (s, 1H), 7.88(s, 1H), 7.68 (d, 2H), 7.37 (d, 2H), 7.23 (d, 1H). LCMS R_(t)=1.12 minin 2.0 min chromatography, 10-80AB, purity 100.00%, MS ESI calcd. forC₁₃H₉F₃N₃O [M+H]⁺ 280.1, found 279.9.

Example 10. Synthesis of Compound 10

A mixture of 5-chlorotriazolo[1,5-a]pyridine (50 mg, 0.33 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(125.45 mg, 0.39 mmol), Pd(t-Bu₃P)₂ (24.96 mg, 0.05 mmol) and K₃PO₄(138.24 mg, 0.65 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) wasstirred at 80° C. for 16 hours to give a brown mixture. After cooling toroom temperature, the suspension was diluted with EtOAc (10 mL),filtered through silica gel, eluted with EtOAc (20 mL). The combinedfiltrates were concentrated to afford the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=20% to 70%) to give the impure product. The impure product waspurified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5□m), A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN; 38-68% B over 6 minutes) to give the product of(44.72 mg, 0.14 mmol, 44% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.84 (d, 1H), 8.24 (d, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.71 (dd,1H), 7.17 (dd, 1H), 4.92 (q, 2H). LCMS R_(t)=1.06 min in 2.0 minchromatography, 10-80AB, purity 100%, MS ESI calcd. for C₁₃H₉F₄N₄O[M+H]⁺ 313.1, found 312.9.

Example 11. Synthesis of Compound 11

Synthesis of A-12

To a mixture of 5-bromo-2,3-difluoro-pyridine (1 g, 5.16 mmol) and3,3-difluorocyclobutanol (668.67 mg, 6.19 mmol) in 1,4-Dioxane (20 mL)was added t-BuOK (1.16 g, 10.31 mmol) at 0° C. Then the mixture wasstirred at 20° C. for 2 hours. After cooling to room temperature, thereaction was quenched with sat. NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (60 mL×2). The combined organic phase was washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0 to 2%) to give the product(1131 mg, 4.01 mmol, 78% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.98 (d, III), 7.52 (dd, 1H), 5.22-5.07 (m, 1H), 3.23-3.05 (m,2H), 2.91-2.70 (m, 2H).

Synthesis of A-13

A mixture of 5-bromo-2-(3,3-difluorocyclobutoxy)-3-fluoro-pyridine (1131mg, 4.01 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3054.73 mg, 12.03 mmol), KOAc (787.04 mg, 8.02 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (491.18 mg, 0.60 mmol) in 1,4-Dioxane (25 mL) wasstirred at 90° C. for 16 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (30 mL) and extracted withEtOAc (60 mL×2). The combined organic phase was washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0 to 2%) to give the product (1430 mg, 1.90mmol, 47% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.25 (s, 1H),7.66 (dd, 1H), 5.31-5.17 (m, 1H), 3.24-3.07 (m, 2H), 2.89-2.71 (m, 2H),1.34 (s, 12H).

Synthesis of 11

A mixture of2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(300.04 mg, 0.91 mmol), 5-chlorotriazolo[1,5-a]pyridine (70 mg, 0.46mmol), Pd(t-Bu₃P)₂ (34.94 mg, 0.07 mmol) and K₃PO₄ (193.54 mg, 0.91mmol) in 1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 80° C. for16 hours under N₂. After cooling to room temperature, the mixture wasdiluted with H₂O (10 mL) and extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The product waspurified by Prep-TLC (PE:EtOAc=1:3) to give the product (16.96 mg, 0.05mmol, 12% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.83 (d, 1H),8.22 (d, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.65 (dd, 1H), 7.16 (dd, 1H),5.33-5.21 (m, 1H), 3.26-3.14 (m, 2H), 2.93-2.78 (m, 2H). LCMS R_(t)=1.09min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₅H₁₂F₃N₄O [M+H]⁺ 321.1, found 321.0.

Example 12. Synthesis of Compound 12

A mixture of2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(106.04 mg, 0.32 mmol), 5-chloro-3-methyl-triazolo[1,5-a]pyridine (30mg, 0.18 mmol), Pd(t-Bu₃P)₂ (13.72 mg, 0.03 mmol) and K₃PO₄ (76 mg, 0.36mmol) in 1,4-Dioxane (3 mL) and Water (0.50 mL) was stirred at 80° C.for 16 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL) and extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=2:1) to give the product(32.01 mg, 0.10 mmol, 53% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.72 (d, 1H), 8.22 (d, 1H), 7.71 (s, 1H), 7.66 (dd, 1H), 7.10 (dd,1H), 5.30-5.16 (m, 1H), 3.27-3.12 (m, 2H), 2.94-2.78 (m, 2H), 2.68 (s,3H). LCMS R_(t)=1.21 min in 2.0 min chromatography, 10-80AB, purity100%, MS ESI calcd. for C₁₆H₁₄F₃N₄O [M+H]⁺ 335.1, found 334.8.

Example 13. Synthesis of Compound 13

Synthesis of A-15

To a mixture of 1-(4-chloro-2-pyridyl)ethanone (400 mg, 2.57 mmol) inHBr/AcOH (5 mL) was added Br₂ (0.2 mL, 3.86 mmol) at 0° C., then themixture was stirred at 25° C. for 2 hours. The mixture was quenched withwater (20 mL), then the mixture was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with sat.Na₂CO₃ (15 mL×3) and brine(15 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (500 mg, 1.30 mmol, 51% yield) as a solid. LCMS Rt=0.75 min in1.5 min chromatography, 5-95AB, purity 61.04%, MS ESI calcd. forC₇H₆BrClNO [M+H+2]⁺ 235.9, found 235.8.

Synthesis of A-16

A mixture of 2-bromo-1-(4-chloro-2-pyridyl)ethanone (100 mg, 0.43 mmol)and AgOTf (547.89 mg, 2.13 mmol) in Methanol (5 mL) was stirred at 25°C. for 48 hours. The mixture was filtered through Celite, and thefiltrate was concentrated to give the crude product (80 mg, 0.22 mmol)as a solid. The crude product was used next step without furtherpurification. LCMS R_(t)=0.63 min in 1.5 min chromatography, 5-95AB,purity 51.01%, MS ESI calcd. for C₈H₉ClNO₂ [M+H]⁺ 186.0, found 185.9.

Synthesis of A-17

A mixture of 1-(4-chloro-2-pyridyl)-2-methoxy-ethanone (80 mg, 0.43mmol) in Ethanol (1.5 mL) was added 4-methylbenzenesulfonohydrazide(120.4 mg, 0.65 mmol), then the mixture was stirred at 25° C. for 2hours. The mixture was added into Morpholine (2.5 mL, 28.7 mmol) at 100°C., then the mixture was stirred at 100° C. for 1 hour. After cooling toroom temperature, the mixture was concentrated to the residue. Theresidue was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=3:1) to give the product (32 mg, 0.16 mmol, 36%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.63 (d, 1H), 7.83 (d,1H), 6.95 (dd, 1H), 4.88 (s, 2H), 3.44 (s, 3H). LCMS Rt=0.62 min in 1.5min chromatography, 5-95AB, purity 96.30%, MS ESI calcd. for C₈H₉ClN₃O[M+H]⁺ 198.0, found 197.9.

Synthesis of 13

A mixture of 5-chloro-3-(methoxymethyl)triazolo[1,5-a]pyridine (30 mg,0.15 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(91.72 mg, 0.30 mmol), Pd(t-Bu₃P)₂ (11.64 mg, 0.02 mmol) and K₃PO₄(64.46 mg, 0.30 mmol) in 1,4-Dioxane (3 mL) and Water (0.50 mL) wasstirred at 80° C. for 16 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (20 mL), and the mixturewas extracted with EtOAc (30 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-TLC (silica gel, PE:DCM:EtOAc=5:5:1) to give theproduct (14.31 mg, 0.04 mmol, 28% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.75 (dd, 1H), 7.72 (s, 1H), 7.31 (d, 1H), 7.21-7.13 (m,2H), 6.97 (dd, 1H), 4.93 (s, 2H), 3.45 (s, 3H), 2.34 (s, 3H). LCMSRt=1.27 min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₆H₁₅F₃N₃O₂[M+H]⁺ 338.1, found 337.8.

Example 14. Synthesis of Compound 14

A mixture of 5-chlorotriazolo[1,5-a]pyridine (100 mg, 0.65 mmol),2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(211.04 mg, 0.78 mmol), Pd(t-Bu₃P)₂ (49.92 mg, 0.10 mmol) and K₃PO₄(276.49 mg, 1.30 mmol) in Water (0.50 mL) and 1,4-Dioxane (5 mL) wasstirred at 80° C. for 16 hours to give a brown mixture. After cooling toroom temperature, the suspension was diluted with EtOAc (10 mL),filtered through silica gel, eluted with EtOAc (20 mL). The combinedfiltrates were concentrated to afford crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 10 μm) A=H₂O(10 mM NH₄HCO₃) and B=CH₃CN; 35-55% B over 6 minutes) to give theproduct (56.29 mg, 33% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.15 (d, 1H), 8.31-8.21 (m, 2H), 7.96-7.89 (m, 2H), 7.55-7.15 (m,4H). LCMS R_(t)=1.01 min in 2 min chromatography, 10-80AB, purity98.63%, MS ESI calcd. for Cl₃H₁₀F₂N₃O [M+H]⁺ 262.1, found 261.9.

Example 15. Synthesis of Compound 15

A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(236.84 mg, 0.78 mmol), Pd(t-Bu₃P)₂ (49.92 mg, 0.10 mmol), K₃PO₄ (276.49mg, 1.3 mmol) and 5-chlorotriazolo[1,5-a]pyridine (100 mg, 0.65 mmol) inWater (0.50 mL) and 1,4-Dioxane (5 mL) was stirred at 80° C. for 16hours to give a brown mixture. After cooling to room temperature, thesuspension was diluted with EtOAc (10 mL), filtered through silica gel,eluted with EtOAc (15 mL). The combined filtrates were concentrated toafford crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 70%) to give impureproduct. The impure product was also purified by Prep-TLC (silica gel,PE:EA=2:1) to give the product (13.96 mg, 7% yield) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=9.17 (d, 1H), 8.72 (s, 1H), 8.34-8.28 (m, 2H),8.24 (s, 1H), 7.63-7.53 (m, 1H), 7.21-7.11 (m, 1H), 5.08 (q, 2H). LCMSR_(t)=1.04 min in 2 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₃H₁₀F₃N₄O [M+H]⁺ 295.1, found 294.9.

Example 16. Synthesis of Compound 16

Synthesis of A-18

A mixture of 5-chlorotriazolo[1,5-a]pyridine (150 mg, 0.98 mmol),[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl]methanol(372.85 mg, 1.17 mmol), Pd(t-Bu₃P)₂ (74.88 mg, 0.15 mmol) and K₃PO₄(414.73 mg, 1.95 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) wasstirred under N₂ at 80° C. for 3 hours to give the brown mixture. Themixture was cooled to room temperature, diluted with EtOAc (10 mL),filtered with silica gel, eluted with EtOAc (20 mL) and concentrated togive the crude product. The crude product was purified by flashchromatograph on silica gel (EtOAc in PE=20% to 50% to 80%) to give theproduct (60 mg, 0.19 mmol, 20% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.81 (d, 1H), 8.13 (s, 1H), 7.94-7.87 (m, 2H), 7.61 (dd,1H), 7.39 (dd, 1H), 7.27-7.24 (m, 1H), 4.90 (s, 2H), 1.99 (br s, 1H).

Synthesis of Compound 16

To a mixture of[5-(triazolo[1,5-a]pyridin-5-yl)-2-(trifluoromethoxy)phenyl]methanol (50mg, 0.16 mmol) in MeCN (2 mL) was added Ag₂O (187.35 mg, 0.81 mmol) andiodomethane (114.75 mg, 0.81 mmol), and the mixture was keep out of thelight and stirred at 25° C. for 32 hours to give the black suspension.The mixture was diluted with MeCN (10 mL), filtered through Celite,eluted with MeCN (20 mL) and the filtrated was concentrated to give thecrude product. The crude product was purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 40-70% Bover 7 minutes) to give the product (18.43 mg, 56.8 mmol, 35% yield) asa solid. ¹H NMR (400MHZ, DMSO-d₆) δ_(H)=9.17 (d, 1H), 8.32 (s, 1H), 8.26(s, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.59-7.45 (m, 2H), 4.56 (s, 2H),3.38 (s, 3H). LCMS R_(t)=1.09 min in 2.0 min chromatography, 10-80AB,purity 100%, MS ESI calcd. for C₁₅H₁₃F₃N₃O₂ [M+H]⁺ 324.1, found 323.9.

Example 17. Synthesis of Compound 17

To a mixture of (S,S)—Co(salen) (107.76 mg, 0.18 mmol) (Jacobsen'scatalyst, cas: 188264-84-8) in Toluene (3 mL) was added AcOH (0.11 mL,1.87 mmol). The mixture was stirred at 20° C. for 30 minutes. Thesolution was concentrated in vacuum to give a crude brown solid. Theresulting catalyst residue was dissolved in 2-(trifluoromethyl)oxirane(10 g, 89.25 mmol). To the mixture was added H₂O (803.66 mg, 44.6 2mmol) at 0° C., then the mixture was stirred at 20° C. for 48 hours. Themixture was distilled at −15° C. under reduced vacuum (˜100 mm Hg), andthe product was collected with a cold trap (−78° C.) to give(2R)-2-(trifluoromethyl)oxirane (3700 mg, 33.02 mmol, 37% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=3.49-3.39 (m, 1H),3.03-2.97 (m, 1H), 2.96-2.90 (m, 1H). To a mixture of(2R)-2-(trifluoromethyl)oxirane (2 g, 17.85 mmol) in Ether (30 mL) wasadded LiAlH₄ (338.69 mg, 8.92 mmol) at 0° C., then the mixture wasstirred at 20° C. for 2 hours. After cooled to 0° C., the mixture wasquenched with water (0.64 g), the mixture was stirred at 20° C. for 30minutes. The mixture was filtered through Celite, eluted with Et₂O (30mL×2), the organic phase was dried over Na₂SO₄, filtered andconcentrated to give the crude product of(2R)-1,1,1-trifluoropropan-2-ol (1100 mg, 9.64 mmol, 54% yield) ascolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=6.03 (d, 1H), 4.16-3.99(m, 1H), 1.20 (d, 3H).

To a solution of (2R)-1,1,1-trifluoropropan-2-ol (1.10 g, 9.64 mmol) inTHF (30 mL) was added NaH (490.93 mg, 12.27 mmol) at 0° C., and themixture was stirred at 0° C. for 30 mins. Then to the mixture was added5-bromo-2,3-difluoro-pyridine (1.70 g, 8.77 mmol), and the mixture wasstirred at 20° C. for 2 hours. From LCMS, desired MS was observed and nostarting material was remained. The mixture was quenched with sat. NH₄Cl(20 mL), then the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with water (30 mL) and brine (30 mL),dried over Na₂SO₄, filtered and concentrated to give the crude productof 5-bromo-3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(2300 mg, 7.99 mmol, 91% yield) as oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.99 (d, 1H), 7.56 (dd, 1H), 5.82-5.69 (m, 1H), 1.54 (d, 3H).

A mixture of5-bromo-3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (2.3g, 7.99 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(6.08 g, 23.96 mmol), KOAc (1.57 g, 15.97 mmol) and Pd(dppf)Cl₂ (876.39mg, 1.2 mmol) in 1,4-Dioxane (60 mL) was stirred at 85° C. for 12 hoursunder N₂. From LCMS, desired MS was observed and no starting materialwas remained. After cooled to r.t., the mixture was concentrated to givethe residue. The residue was diluted with H₂O (30 mL), and the mixturewas extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) togive the product of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(4200 mg, 12.53 mmol) as oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.25 (d,1H), 7.70 (dd, 1H), 5.95-5.82 (m, 1H), 1.54 (d, 3H), 1.34 (s, 12H).

A mixture of 5-chlorotriazolo[1,5-a]pyridine (100 mg, 0.65 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(IR)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (327.31 mg, 0.98 mmol),Pd(t-Bu₃P)₂ (49.92 mg, 0.10 mmol) and K₃PO₄ (276.49 mg, 1.3 mmol) in1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred under N₂ at 80° C.for 16 hours to give the brown mixture. The mixture was cooled to roomtemperature, diluted with EtOAc (10 mL), filtered with silica gel,eluted with EtOAc (20 mL) and concentrated to give the crude product.The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm×30mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 60-90% B over 7 minutes) togive the product (87.3 mg, 41% yield) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ_(H)=9.20 (d, 1H), 8.57 (d, 1H), 8.43-8.34 (m, 2H), 8.27 (s,1H), 7.61 (dd, 1H), 6.07-5.93 (m, 1H), 1.54 (d, 3H). LCMS R_(t)=1.10 minin 2.0 min chromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₄H₁₁F₄N₄O [M+H]⁺ 327.1, found 326.9.

Example 18. Synthesis of Compound 18

To a solution of (R,R)—Co(salen) (550 mg, 0.91 mmol) (Jacobsen'scatalyst, cas: 176763-62-5) in Toluene (10 mL) was added AcOH (0.5 5 mL,9.6 mmol), and the mixture was stirred at 15° C. open to air for 1 hour.Then the mixture was concentrated, and the brown residue was dissolvedin 2-(trifluoromethyl)oxirane (50 g, 446.23 mmol). To the mixture wasadded H₂O (4.4 mL, 244.44 mmol) at 0° C. and the mixture was stirred at15° C. for 56 hours. The mixture was distilled at −15° C. under reducedvacuum (˜100 mm Hg), and the product was collected with a cold trap(−78° C.) to give the product of (2S)-2-(trifluoromethyl)oxirane (18000mg, 160.64 mmol, 36% yield) as colorless liquid.

Note: the product was ring-opened with BnNH₂ (1 eq), and the resultedsolid triturated from n-hexane and analyzed by SFC to show the ee % wasabout 86%. Method: Column: Chiral CD-Ph 250×4.6 mm I.D., 5 μm; Mobilephase: from 10% to 80% of B in A; A: Water with 0.069% TFA B:Acetonitrile; Flow rate: 0.8 mL/min; Column Temperature: 30° C. ¹H NMR(400 MHz, CDCl₃) δ_(H)=3.47-3.40 (m, 1H), 3.02-2.97 (m, 1H), 2.96-2.91(m, 1H).

To a mixture of (2S)-2-(trifluoromethyl)oxirane (18 g, 160.64 mmol) inEther (150 mL) was added LiAlH₄ (3.05 g, 80.32 mmol) at 0° C., then themixture was stirred at 15° C. for 1 hours. After cooled to 0° C., themixture was quenched with water (4 mL), and the mixture was stirred at20° C. for 30 minutes. The mixture was filtered through Celite, elutedwith Et₂O (100 mL×3), and the organic phase was dried over Na₂SO₄,filtered and concentrated to give the crude product of(2S)-1,1,1-trifluoropropan-2-ol (8000 mg, 70.13 mmol, 44% yield) ascolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=6.03 (d, 1H), 4.14-3.97(m, 1H), 1.20 (d, 3H).

To a solution of (2S)-1,1,1-trifluoropropan-2-ol (8 g, 70.13 mmol) inTHF (100 mL) was added NaH (2.81 g, 70.13 mmol) at 0° C., and themixture was stirred at 0° C. for 30 mins. Then to the mixture was added5-bromo-2,3-difluoro-pyridine (13.6 g, 70.13 mmol), and the mixture wasstirred at 15° C. for 3 hours. From TLC (PE), no starting material(Rf=0.5, UV) was remained and a new spot (Rf=0.6, UV) was observed. Themixture was diluted with sat.NH₄Cl (50 mL) and extracted with EtOAc (100mL×2). The combined organic phase was washed with H₂O (30 mL) and brine(30 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct of5-bromo-3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (18000mg, 62.49 mmol, 89% yield) as oil.

A mixture of5-bromo-3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (3 g,10.42 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(7.93 g, 31.25 mmol), KOAc (3.07 g, 31.25 mmol) and Pd(dppf)Cl₂ (1.14 g,1.56 mmol) in 1,4-Dioxane (150 mL) was stirred at 90° C. for 16 hours.From LCMS, desired MS was observed and no starting material wasremained. After cooled to r.t., the mixture was concentrated to give thecrude product. The crude product was diluted with PE (200 mL), filteredthrough silica gel and eluted with PE (150 mL×2). The filtrate wasconcentrated to give the crude product of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(5000 mg, 14.92 mmol, crude) as oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.17(d, 1H), 7.62 (dd, 1H), 5.89-5.72 (m, 1H), 1.46 (d, 3H), 1.26 (s, 12H).

A mixture of 5-chlorotriazolo[1,5-a]pyridine (80 mg, 0.52 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (261.85 mg, 0.78 mmol),Pd(t-Bu₃P)₂ (39.93 mg, 0.08 mmol) and K₃PO₄ (221.19 mg, 1.04 mmol) in1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 80° C. for 16hours to give the brown mixture. The mixture was cooled to roomtemperature, diluted with EtOAc (10 mL), filtered through silica gel,eluted with EtOAc (20 mL) and concentrated to give the crude product.The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 48-68% B over 6 minutes)to give the product (81.84 mg, 0.24 mmol, 47% yield) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=9.20 (d, 1H), 8.57 (d, 1H), 8.42-8.35 (m, 2H),8.27 (s, 1H), 7.61 (dd, 1H), 6.08-5.94 (m, 1H), 1.54 (d, 3H). LCMSR_(t)=1.10 min in 2.0 min chromatography, 10-80AB, purity 97.94%, MS ESIcalcd. for C₁₄H F₄N₄O [M+H]⁺ 327.1, found 326.9.

Example 19. Synthesis of Compound 19

Synthesis of A-20

To a mixture of 4-bromophenol (384.15 mg, 2.22 mmol),3,3-difluorocyclobutanol (200 mg, 1.85 mmol) and Ph₃P (1.46 g, 5.55mmol) in Toluene (15 mL) was added DEAD (966.69 mg, 5.55 mmol) under N₂.Then the mixture was heated and stirred at 100° C. for 16 hours. Themixture was concentrated, and the residue was diluted with EtOAc (10mL), then washed with H₂O (10 mL) and brine (10 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (EtOAc in PE=10:1)to give the product (80 mg, 0.30 mmol, 16% yield) as an oil. ¹H NMR (400MHz, CDCl₃) δ_(H)=7.39 (d, 2H), 6.70 (d, 2H), 4.70-4.53 (m, 1H),3.17-2.99 (m, 2H), 2.84-2.64 (m, 2H).

Synthesis of A-21

A brown mixture of 1-bromo-4-(3,3-difluorocyclobutoxy)benzene (80 mg,0.30 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(115.83 mg, 0.46 mmol), Pd(dppf)Cl₂ (33.38 mg, 0.05 mmol) and KOAc(59.69 mg, 0.61 mmol) in 1,4-Dioxane (2 mL) was stirred at 80° C. for 16hours under N₂. The mixture was cooled to room temperature, diluted withEtOAc (5 mL), filtered with silica gel, eluted with EtOAc (10 mL) andconcentrated to give the crude product. The crude product was purifiedby Prep-TLC (EtOAc in PE=10:1) to give the product (80 mg, 0.26 mmol,85% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.76 (d, 2H), 6.80(d, 2H), 4.74-4.63 (m, 1H), 3.16-3.04 (m, 2H), 2.83-2.69 (m, 2H), 1.34(s, 12H).

Synthesis of 19

A mixture of 5-chlorotriazolo[1,5-a]pyridine (40 mg, 0.26 mmol),2-[4-(3,3-difluorocyclobutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(80 mg, 0.26 mmol), Pd(t-Bu₃P)₂ (19.97 mg, 0.04 mmol) and K₃PO₄ (110.59mg, 0.52 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at80° C. for 2 hours to give the brown mixture. The mixture was cooled toroom temperature, diluted with EtOAc (10 mL), filtered with silica gel,eluted with EtOAc (20 mL) and concentrated to give the crude product.The crude product was purified by Prep-TLC (EtOAc in PE=1:1) to give theproduct (3.36 mg, 0.011 mmol, 4.3% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.79 (d, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.62 (d, 2H),7.24 (dd, 1H), 6.96 (d, 2H), 4.81-4.68 (m, 1H), 3.22-3.10 (m, 2H),2.90-2.76 (m, 2H). LCMS R_(t)=1.10 min in 2.0 min chromatography,10-80AB, purity 100%, MS ESI calcd. for C₁₆H₁₄F₂N₃O [M+H]⁺ 302.1, found301.9.

Example 20. Synthesis of Compound 20

Synthesis of A-23

To a solution of 4-bromopyridine-2-carbonitrile (5 g, 27.32 mmol) in THF(80 mL) at 0° C. was added MeMgBr (18.21 mL, 54.64 mmol) dropwise. Thereaction mixture was stirred at 0° C. for 2 hours to give a brownmixture. The reaction mixture was quenched with 1N HCl (150 mL),extracted with EtOAc (100 mL×2). The combined organic phase was washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product (4700 mg, 86% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.50 (d, 1H), 8.20 (d, 1H), 7.64 (dd, 1H), 2.71 (s, 3H).

Synthesis of A-24

To a mixture of 1-(4-bromo-2-pyridyl)ethanone (2 g, 10 mmol) in HBr/AcOH(20 mL, 10 mmol) was added Br₂ (0.67 mL, 13 mmol) at 0° C., then themixture was stirred at 15° C. for 2 hours. The mixture was quenched withwater (50 mL), then the mixture was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with sat. Na₂CO₃ (30 mL×3) and brine(15 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (2200 mg, 7.89 mmol, 79% yield) as a solid. LCMS R_(t)=0.82 minin 1.5 min chromatography, 5-95AB, purity 70.74%, MS ESI calcd. forC₇H₆Br₂NO [M+H+2]⁺ 279.9, found 279.7.

Synthesis of A-25

A mixture of 2-bromo-1-(4-bromo-2-pyridyl)ethanone (2.2 g, 7.89 mmol)and AgOTf (10.13 g, 39.44 mmol) in Methanol (30 mL) was stirred at 25°C. for 72 hours to give a black mixture. The mixture was treated withbrine (200 mL) and EtOAc (200 mL). The organic phase was separated, thenwashed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash chromatography on silica gel (EtOAc inPE=0% to 10% to 25%) to give the product (900 mg, 3.91 mmol, 50% yield)as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.46 (d, 1H), 8.24 (d, 1H),7.71-7.65 (m, 1H), 5.02 (s, 2H), 3.55 (s, 3H).

Synthesis of A-26

A mixture of 1-(4-bromo-2-pyridyl)-2-methoxy-ethanone (800 mg, 3.48mmol) and 4-methylbenzenesulfonohydrazide (971.38 mg, 5.22 mmol) inEthanol (20 mL) was stirred at 15° C. for 16 hours to give a mixture.The reaction mixture was concentrated to give the crude product (1600mg, 1.46 mmol, 42% yield) as a solid. LCMS R_(t)=0.86 min in 1.5 minchromatography, 5-95AB, purity 36.40%, MS ESI calcd. for C₁₅H₁₇BrN₃O₃S[M+H+2]⁺ 400.0, found 399.8.

Synthesis of A-27

A mixture ofN-[[1-(4-bromo-2-pyridyl)-2-methoxy-ethylidene]amino]-4-methyl-benzenesulfonamide(1.6 g, 4.02 mmol) in morpholine (20 mL, 229.57 mmol) was stirred at100° C. for 2 hours to give a mixture. After cooling to roomtemperature, the reaction mixture was concentrated. The residue waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to20%) to give the product (450 mg, 1.86 mmol, 46% yield) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=8.57 (d, 1H), 8.06-7.99 (m, 1H), 7.06 (dd,1H), 4.88 (s, 2H), 3.44 (s, 3H).

Synthesis of 20

A mixture of 5-bromo-3-(methoxymethyl)triazolo[1,5-a]pyridine (150 mg,0.62 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(397.92 mg, 1.24 mmol), K₃PO₄ (263.11 mg, 1.24 mmol) and Pd(t-Bu₃P)₂(63.33 mg, 0.12 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) under N₂was stirred at 80° C. for 16 hours to give a brown mixture. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(10 mL), and filtered through a Celite pad, eluted with EtOAc (10 mL).The filtrate was concentrated. The residue was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;40-55% B over 7 minutes) to give the product (79.72 mg, 0.22 mmol, 79%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.79 (d, 1H), 8.25 (d,1H), 7.94 (s, 1H), 7.72 (dd, 1H), 7.17 (dd, 1H), 4.98-4.88 (m, 4H), 3.47(s, 3H). LCMS R_(t)=1.10 min in 2.0 min chromatography, 10-80AB, purity100%, MS ESI calcd. for C₁₅H₁₃F₄N₄O₂[M+H]⁺ 357.1, found 357.0.

Example 21. Synthesis of Compound 21

A mixture of 5-bromo-3-methyl-triazolo[1,5-a]pyridine (200 mg, 0.94mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(379.27 mg, 1.13 mmol), K₃PO₄ (400.47 mg, 1.89 mmol) and Pd(t-Bu₃P)₂(96.4 mg, 0.19 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) under N₂was stirred at 80° C. for 16 hours to give a brown mixture. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(10 mL), and filtered through a Celite pad, eluted with EtOAc (10 mL).The filtrate was concentrated. The residue was purified by Prep-HPLC(Agela DuraShell (150 mm×25 mm 5 μm), A=H₂O (0.04% NH₃H₂O+10 mM NH₄HCO₃)and B=CH₃CN; 45-75% B over 8.5 minutes) to give impure product, theimpure was triturated from CH₂Cl₂/n-haxane (1 mL: 4 mL) to give theproduct (44.27 mg, 0.13 mmol, 14% yield) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ_(H)=9.06 (d, 1H), 8.59 (d, 1H), 8.46-8.34 (m, 2H), 7.55 (dd,1H), 6.08-5.95 (m, 1H), 2.59 (s, 3H), 1.54 (d, 3H). LCMS R_(t)=1.08 minin 2.0 min chromatography, 10-80AB, purity 98.52%, MS ESI calcd. forC₁₅H₁₃F₄N₄O [M+H]⁺ 341.1, found 340.9.

Example 22. Synthesis of Compound 22

Synthesis of A-30

A mixture of 1-(4-bromo-2-pyridyl)ethanone (2.7 g, 13.5 mmol) and4-methylbenzenesulfonohydrazide (3.77 g, 20.25 mmol) in Ethanol (30 mL)was stirred at 15° C. for 2 hours to give a brown mixture. The reactionmixture was concentrated to give the crude product (6000 mg, 12.35 mmol,92% yield) as a solid. LCMS R_(t)=0.84 min in 1.5 min chromatography,5-95AB, purity 75.82%, MS ESI calcd. for C₁₄H₁₅BrN₃O₂S [M+H+2]⁺ 370.0,found 369.9.

Synthesis of A-28

A mixture ofN-[1-(4-bromo-2-pyridyl)ethylideneamino]-4-methyl-benzenesulfonamide (6g, 16.29 mmol) in Morpholine (30 mL, 344.35 mmol) was stirred at 100° C.for 2 hours to give a brown mixture. After cooling to room temperature,the reaction mixture was concentrated. The residue was purified by flashchromatography on silica gel (EtOAc in PE=0% to 20% to 30%) to give theproduct (2200 mg, 10.38 mmol, 64% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.52 (d, 1H), 7.81 (s, 1H), 7.00-6.98 (m, 1H), 2.60 (s,3H).

Synthesis of 22

A mixture of 5-bromo-3-methyl-triazolo[1,5-a]pyridine (200 mg, 0.94mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (379.27 mg, 1.13 mmol),K₃PO₄ (400.47 mg, 1.89 mmol) and Pd(t-Bu₃P)₂ (96.4 mg, 0.19 mmol) in1,4-Dioxane (4 mL) and Water (0.40 mL) under N₂ was stirred at 80° C.for 16 hours to give a brown mixture. After cooling to room temperature,the reaction mixture was diluted with EtOAc (10 mL), and filteredthrough a Celite pad, eluted with EtOAc (10 mL). The filtrate wasconcentrated. The residue was purified by Prep-HPLC (Waters Xbridge (150mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 46-66% B over 6minutes) to give the product (190.14 mg, 0.55 mmol, 58% yield) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.07 (d, 1H), 8.59 (d, 1H),8.46-8.35 (m, 2H), 7.56 (dd, 1H), 6.07-5.96 (m, 1H), 2.59 (s, 3H), 1.54(d, 3H). LCMS R_(t)=1.21 min in 2.0 min chromatography, 10-80AB, purity100%, MS ESI calcd. for C₁₅H₁₃F₄N₄O [M+H]⁺ 341.1, found 340.9.

Example 23. Synthesis of Compound 23-1 and 23-2

A mixture of2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(437.77 mg, 1.56 mmol), Pd(t-Bu₃P)₂ (99.83 mg, 0.20 mmol), K₃PO₄ (552.97mg, 2.60 mmol), and 5-chlorotriazolo[1,5-a]pyridine (200 mg, 1.30 mmol)in 1,4-Dioxane (3 mL) and Water (0.30 mL) was stirred at 80° C. for 16hours. After cooling to room temperature, the mixture was concentratedto the residue. The residue was diluted with H₂O (20 mL) and extractedwith EtOAc (20 mL×2). The combined organic phase was washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 37-57%B over 7 minutes) to give the product (30 mg, 0.11 mmol, 8% yield) as asolid. The product was analyzed by SFC and showed two peaks (Peak 1:Rt=4.89 min, Peak 2: Rt=5.47 min).

Method: Column: Chiralpak AD-3 150×4.6 mm I.D, 3 μm Mobile phase: A: CO₂B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C. ¹H NMR CDCl₃ 400 MHz δ_(H)=8.80 (d, 1H), 8.11 (s, 1H),7.88 (s, 1H), 7.63 (d, 2H), 7.38 (d, 2H), 7.26-7.23 (m, 1H), 2.93-2.77(m, 1H), 1.98-1.85 (m, 1H), 1.76-1.64 (m, 1H). The product was analyzedby SFC showed two peaks (Peak 1: Rt=4.89 min, Peak 2: Rt=5.47 min).Method: Column: Chiralpak AD-3 150×4.6 mm I.D, 3 m Mobile phase: A: CO₂B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C.

The product was purified by SFC (Phenomenex-Amylose-1 (250 mm×30 mm, 5μm); A=CO₂ and B=MEOH (0.1% NH₃H₂O); 38° C.; 50 mL/min; 40% B; 8 minrun; 7 injections, Rt of peak 1=5.5 min, Rt of peak 2=6.5 min) to givethe product of5-[4-[(1R)-2,2-difluorocyclopropyl]phenyl]triazolo[1,5-a]pyridine (5.48mg, 0.02 mmol, 21.68% yield, 98.92% purity) (Peak 1, Rt=4.89 min in SFC:23-1) as a solid and5-[4-[(1S)-2,2-difluorocyclopropyl]phenyl]triazolo[1,5-a]pyridine (8.78mg, 32.20 μmol, 29.11% yield, 99.45% purity) (Peak 2: Rt=5.47 min inSFC: 23-2) as a solid. 23-1: ¹H NMR (400 MHz, MeOD-d₄) δ_(H)=8.94 (d,1H), 8.22-8.12 (m, 2H), 7.76 (d, 2H), 7.51 (dd, 1H), 7.41 (d, 2H),3.00-2.85 (m, 1H), 1.99-1.87 (m, 1H), 1.86-1.75 (m, 1H). LCMS R_(t)=1.00min in 2 min chromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₅H₁₂F₂N₃ [M+H]⁺ 272.1, found 271.9. 23-2: ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.14 (d, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.83 (d, 2H), 7.55-7.53(m, 1H), 7.43 (d, 2H), 2.07-2.00 (m, 1H), 3.11-3.05 (m, 2H). LCMSR_(t)=1.05 min in 2 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₅H₁₂F₂N₃ [M+H]⁺ 272.1, found 271.9.

Note: the enantiomers were randomly assigned.

Example 24. Synthesis of Compound 24

To a solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (3 g, 23.42 mmol)in THF (10 mL) was added NaH (936.84 mg, 23.42 mmol). Then to themixture was added 5-bromo-2,3-difluoro-pyridine (4.54 g, 23.42 mmol),and the mixture was stirred at 80° C. for 16 hours. After cooled tor.t., the mixture was diluted with H₂O (10 mL) and extracted with EtOAc(10 mL×2). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 2%) to give A-31b (2800 mg, 9.27 mmol, 40% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.99 (d, 1H), 7.54 (dd,1H), 1.80 (d, 6H).

A mixture of5-bromo-3-fluoro-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (1.5 g,4.97 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.89 g, 7.45 mmol), Pd(dppf)Cl₂ (545.03 mg, 0.74 mmol) and KOAc (974.71mg, 9.93 mmol) in 1,4-Dioxane (20 mL) was stirred at 90° C. for 16 hoursto give a brown mixture. After cooling to r.t., the suspension wasdiluted with EtOAc (10 mL), filtered through silica gel, eluted withEtOAc (20 mL). The filtrate was concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 10%) to give A-31d (1000 mg, 2.86 mmol, 58% yield) asan off-white solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.26 (d, 1H), 7.67(dd, 1H), 1.83 (s, 6H), 1.34 (s, 12H).

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(411.81 mg, 1.17 mmol), 5-chlorotriazolo[1,5-a]pyridine (150 mg, 0.98mmol), Pd(t-Bu₃P)₂ (74.88 mg, 0.15 mmol) and K₃PO₄ (414.73 mg, 1.95mmol) in 1,4-Dioxane (3 mL) and Water (0.30 mL) was stirred at 85° C.for 16 hours. After cooling to room temperature, the suspension wasdiluted with EtOAc (10 mL), filtered through silica gel, eluted withEtOAc (20 mL). The combined filtrates were concentrated to afford crudeproduct. The crude product was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 48-68% B over 7minutes) to give the product (127.17 mg, 0.37 mmol, 38% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.83 (d, 1H), 8.23 (d, 1H), 8.15(s, 1H), 7.85 (s, 1H), 7.66 (dd, 1H), 7.17 (dd, 1H), 1.88 (s, 6H). LCMSR_(t)=1.22 min in 2 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₅H₁₃F₄N₄O [M+II]⁺ 341.1, found 340.9.

Example 25. Synthesis of Compound 25

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(262.04 mg, 0.75 mmol), 5-chloro-3-methyl-triazolo[1,5-a]pyridine (150mg, 0.89 mmol), Pd(t-Bu₃P)₂ (68.61 mg, 0.13 mmol), and K₃PO₄ (380.01 mg,1.79 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 85°C. for 16 hours. After cooling to room temperature, the suspension wasdiluted with EtOAc (10 mL), filtered through silica gel, eluted withEtOAc (15 mL). The combined filtrates were concentrated to afford crudeproduct. The crude product was purified by Prep-HPLC (Xtimate C18 (150mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 54-70% B over 9minutes) to give the product (92.98 mg, 0.26 mmol, 29% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.73 (d, 1H), 8.24 (d, 1H), 7.72(s, 1H), 7.67 (dd, 1H), 7.11 (d, 1H), 2.68 (s, 3H), 1.88 (s, 6H). LCMSR_(t)=1.33 min in 2 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₆H₁₅F₄N₄O [M+H]⁺ 355.1, found 355.0.

Example 26. Synthesis of Compound 26

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(149.34 mg, 0.43 mmol), 5-bromo-3-(methoxymethyl)triazolo[1,5-a]pyridine(85.74 mg, 0.35 mmol), Pd(t-Bu₃P)₂ (27.15 mg, 0.05 mmol), and K₃PO₄(150.40 mg, 0.71 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) wasstirred at 85° C. for 16 hours. After cooling to room temperature, thesuspension was diluted with EtOAc (10 mL), filtered through silica gel,eluted with EtOAc (15 mL). The combined filtrates were concentrated toafford crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;46-66% B over 9 minutes) to give the product of (50.31 mg, 0.13 mmol,37% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.78 (d, 1H), 8.25(d, 1H), 7.93 (s, 1H), 7.68 (dd, 1H), 7.17 (dd, 1H), 4.96 (s, 2H), 3.47(s, 3H), 1.88 (s, 6H). LCMS R_(t)=1.32 min in 2 min chromatography,10-80AB, purity 100%, MS ESI calcd. for C₁₇H₁₇F₄N₄O₂[M+H]⁺ 385.1, found385.0.

Example 27. Synthesis of Compound 27

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (122.09 mg, 0.36 mmol),5-chloro-3-(methoxymethyl)triazolo[1,5-a]pyridine (60 mg, 0.30 mmol),Pd(t-Bu₃P)₂ (23.27 mg, 0.05 mmol), and K₃PO₄ (128.91 mg, 0.61 mmol) in1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 85° C. for 16hours. After cooling to room temperature, the suspension was dilutedwith EtOAc (10 mL), filtered through silica gel, eluted with EtOAc (20mL). The combined filtrates were concentrated to afford crude product.The crude product was purified by purified by Prep-HPLC (Xtimate C18(150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 41-66% B over 9minutes) to give the product (20.87 mg, 56.30 μmol, 19% yield) as asolid. ¹H NMR (400 MHz, CDCl₃+D₂O) δ_(H)=8.79 (d, 1H), 8.24 (d, 1H),7.94 (s, 1H), 7.78-7.65 (m, 1H), 7.18 (d, 1H), 6.03-5.75 (m, 1H), 4.96(s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS R_(t)=1.27 min in 2 minchromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₆H₁₅F₄N₄O₂[M+H]⁺ 371.1, found 371.0.

Example 28. Synthesis of Compound 28

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (99.67 mg, 0.30 mmol),5-bromo-3-(methoxymethyl)triazolo[1,5-a]pyridine (60 mg, 0.25 mmol),Pd(t-Bu₃P)₂ (19 mg, 0.04 mmol), and K₃PO₄ (105.24 mg, 0.50 mmol) in1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 85° C. for 16hours. After cooling to room temperature, the suspension was dilutedwith EtOAc (10 mL), filtered through silica gel, eluted with EtOAc (20mL). The combined filtrates were concentrated to afford crude product.The crude product was purified by purified by Prep-HPLC (Xtimate C18(150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 41-66% B over 9minutes) to give the product (13.98 mg, 0.04 mmol, 15% yield) as asolid. ¹H NMR (400 MHz, CDCl₃+D₂O) δ_(H)=8.79 (d, 1H), 8.24 (d, 1H),7.93 (s, 1H), 7.71 (dd, 1H), 7.18 (d, 1H), 5.98-5.79 (m, 1H), 4.96 (s,2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS R_(t)=1.22 min in 2 minchromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₆H₁₅F₄N₄O₂[M+H]⁺ 371.1, found 371.0.

Example 29. Synthesis of Compound 29

To a colorless mixture of cyclobutanone (500 mg, 7.13 mmol) andtrimethyl(trifluoromethyl)silane (1.32 g, 9.27 mmol) in THF (10 mL) wasadded TBAF (0.07 mL, 0.07 mmol) at 0° C., then the mixture was stirredat 20° C. for 2 hours. The mixture was neutralized with IM HCl (10 mL),then the mixture was stirred at 20° C. for 1 hours. Later on the mixturewas extracted with DCM (30 mL×2). The combined organic phase was washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product A-27b (450 mg, 3.21 mmol, 45%yield) as oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=6.40 (s, 1H), 2.38-2.27(m, 2H), 2.18-2.04 (m, 2H), 1.90-1.79 (m, 1H), 1.74-1.60 (m, 1H).

To a solution of 1-(trifluoromethyl)cyclobutanol (216.67 mg, 1.55 mmol)in THF (10 mL) was added NaH (61.86 mg, 1.55 mmol) at 0° C., and themixture was stirred for 30 min. Then to the mixture was added5-bromo-2,3-difluoro-pyridine (300 .mg, 1.55 mmol), and the mixture wasstirred at 80° C. for 4 hours. After cooling to r.t., the mixture waspour into ice water and stirred for 30 mins. Then the mixture wasdiluted with sat.NH₄Cl (20 mL) and extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product A-27c. ¹H NMR (400MHz, DMSO-d₆) δ_(H)=8.21 (dd, 1H), 8.16 (d, 1H), 2.88-2.76 (m, 2H),2.65-2.56 (m, 2H), 1.97-1.88 (m, 1H), 1.87-1.76 (m, 1H).

A brown mixture of5-bromo-3-fluoro-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (400 mg,1.27 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(323.42 mg, 1.27 mmol), Pd(dppf)Cl₂ (139.78 mg, 0.19 mmol) and KOAc(249.98 mg, 2.55 mmol) in 1,4-Dioxane (20 mL) was stirred at 90° C. for16 hours under N₂. The mixture was cooled to r.t. and concentrated. Theresidue was diluted with EtOAc/PE (1:10, 20 mL), filtered through silicagel, eluted with EtOAc/PE (1:10, 50 mL) and concentrated to give thecrude product A-27d (500 mg, crude) as oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.27 (d, 1H), 7.68 (dd, 1H), 2.99-2.84 (m, 2H), 2.77-2.64 (m, 2H),2.02-1.91 (m, 2H), 1.36-1.33 (m, 12H).

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(175.43 mg, 0.49 mmol),5-chloro-3-(methoxymethyl)triazolo[1,5-a]pyridine (80 mg, 0.40 mmol),Pd(t-Bu₃P)₂ (31.03 mg, 0.06 mmol), and K₃PO₄ (171.89 mg, 0.81 mmol) in1,4-Dioxane (4 mL) and Water (0.40 mL) was stirred at 85° C. for 16hours. After cooling to room temperature, the suspension was dilutedwith EtOAc (10 mL), filtered through silica gel, eluted with EtOAc (20mL). The combined filtrates were concentrated to afford crude product.The crude product was purified by Prep-HPLC (Xtimate C18 (150 mm×25 mm,5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 48-78% B over 7 minutes) togive the product (32.94 mg, 0.08 mmol, 21% yield) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H)=8.78 (dd, 1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.68(dd, 1H), 7.17 (dd, 1H), 4.95 (s, 2H), 3.47 (s, 3H), 2.99-2.86 (m, 2H),2.81-2.71 (m, 2H), 2.10-1.92 (m, 2H). LCMS R_(t)=1.31 min in 2 minchromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₈H₁₇F₄N₄O₂[M+H]⁺ 397.1, found 397.1.

Example 30. Synthesis of Compound 30

Synthesis of A-32

To a mixture of5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]triazolo[1,5-a]pyridine(1.6 g, 4.9 mmol) in THF (70 mL) was added n-BuLi (4.9 mL, 12.26 mmol)at −78° C. under N₂, then the mixture was stirred at −78° C. for 1 hour.To the mixture was added chloro(trimethyl)silane (1.86 g, 17.16 mmol),then the mixture was stirred at −78° C. for 1 hour. The mixture wasquenched with sat. NH₄Cl (100 mL), then the mixture was extracted withEtOAc (50 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by silica gel column (EtOAc inPE=0% to 5% to 10%) to give the product (1120 mg, 2.30 mmol, 47% yield)as a solid. LCMS R_(t)=1.05 min in 1.5 min chromatography, 5-95AB,purity 96.60%, MS ESI calcd. for C₂₀H₂₇F₄N₄OSi₂ [M+H]⁺ 471.2, found471.2.

Synthesis of A-33

To a mixture of[5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-4-trimethylsilyl-3-pyridyl]triazolo[1,5-a]pyridin-7-yl]-trimethyl-silane(700 mg, 1.49 mmol) in THF (40 mL) was added n-BuLi (0.71 mL, 1.78 mmol)at −78° C. under N₂. Then the mixture was stirred at −78° C. for 1 hour.To the mixture was added I₂ (755.05 mg, 2.97 mmol), then the mixture wasstirred at −78° C. for 1 hour. The mixture was quenched with sat. NH₄Cl(30 mL), then the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%to 5%) to give the product (430 mg, 0.50 mmol, 34% yield) as an oil.LCMS R_(t)=1.17 min in 1.5 min chromatography, 5-95AB, purity 69.42%, MSESI calcd. for C₂₀H₂₆F₄IN₄OSi₂ [M+H]⁺ 597.1, found 597.1.

Synthesis of A-34

A mixture of 1,10-phenanthroline, trifluoromethyl copper (225.46 mg,0.72 mmol) and[3-fluoro-5-(3-iodo-7-trimethylsilyl-triazolo[1,5-a]pyridin-5-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-4-pyridyl]-trimethyl-silane(430 mg, 0.72 mmol) in DMF (4.81 mL) was stirred at 45° C. for 24 hoursin sealed tube under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (10 mL×2)and brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-TLC (silicagel, PET/EtOAc=5/1) to give the impure product (200 mg, 0.37 mmol) as anoil, which was used directly without any further purification.

Synthesis of 30

To a mixture of[3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-[3-(trifluoromethyl)-7-trimethylsilyl-triazolo[1,5-a]pyridin-5-yl]-4-pyridyl]-trimethyl-silane(200 mg, 0.37 mmol) in THF (20 mL) was added TBAF (1.86 mL, 1.86 mmol),then the mixture was stirred at 20° C. for 1 hour. The mixture wasdiluted with H₂O (20 mL), and the mixture was extracted with EtOAc (30mL×2). The combined organic phase was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=4:1) to give the impure product, which was purified byPrep-HPLC [Boston Prime C18 (150 mm×30 mm, 5 μm), A=H₂O (0.05% NH₄OH)and B=CH₃CN; 64-94% B over 8 minutes] to give the product (13.78 mg,34.2 μmol, 9% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.90 (dd,1H), 8.27 (d, 1H), 7.94 (s, 1H), 7.72 (dd, 1H), 7.32 (dd, 1H), 5.97-5.85(m, 1H), 1.60 (d, 3H). LCMS R_(t)=2.10 min in 3.0 min chromatography,30-90CD, purity 98.18%, MS ESI calcd. for C₁₅H₁₀F₇N₄O [M+H]⁺ 395.1,found 395.1.

Example 31. Synthesis of Compound 31

Synthesis of A-35

To a mixture of5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]triazolo[1,5-a]pyridine(1.1 g, 3.37 mmol) in THF (40 mL) was added n-BuLi (3.37 mL, 8.43 mmol)at −78° C. under N₂, then the mixture was stirred at −78° C. for 2hours. To the mixture was added chloro(trimethyl)silane (1.28 g, 11.8mmol), then the mixture was stirred at −78° C. for 2 hours. The mixturewas quenched with sat. NH₄Cl (100 mL), then the mixture was extractedwith EtOAc (100 mL×2). The combined organic phase was washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by silica gel column (EtOAc inPE=0% to 10% to 20%) to give the product (800 mg, 1.86 mmol, 55% yield)as a solid. LCMS R_(t)=0.95 min in 1.5 min chromatography, 5-95AB,purity 92.57%, MS ESI calcd. for C₁₇H₁₉F₄N₄OSi [M+H]⁺ 399.1, found399.1.

Synthesis of A-36

To a mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]triazolo[1,5-a]pyridin-7-yl]-trimethyl-silane(800 mg, 2.01 mmol) in THF (40 mL) was added n-BuLi (0.96 mL, 2.41 mmol)at −78° C. under N₂, then the mixture was stirred at −78° C. for 1 hour.To the mixture was added chloro(trimethyl)silane (654.41 mg, 6.02 mmol),then the mixture was stirred at −78° C. for 1 hour. The mixture wasquenched with sat. NH₄Cl (30 mL), then the mixture was extracted withEtOAc (50 mL×2). The combined organic phase was washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by silica gel column (EtOAc inPE=0% to 10% to 15%) to give the product (660 mg, 1.30 mmol, 65% yield)as a solid. LCMS R_(t)=1.04 min in 1.5 min chromatography, 5-95AB,purity 92.38%, MS ESI calcd. for C₂₀H₂₇F₄N₄OSi₂ [M+H]⁺ 471.2, found471.2.

Synthesis of A-37

To a mixture of[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-4-trimethylsilyl-3-pyridyl]triazolo[1,5-a]pyridin-7-yl]-trimethyl-silane(500 mg, 1.06 mmol) in THF (30 mL) was added n-BuLi (0.51 mL, 1.27 mmol)at −78° C. under N₂. Then the mixture was stirred at −78° C. for 1 hour.To the mixture was added I₂ (539.32 mg, 2.12 mmol), then the mixture wasstirred at −78° C. for 1 hour. The mixture was quenched with sat. NH₄Cl(30 mL), then the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%to 5%) to give the product (320 mg, 0.36 mmol, 33% yield) as an oil.LCMS R_(t)=1.17 min in 1.5 min chromatography, 5-95AB, purity 66.24%, MSESI calcd. for C₂₀H₂₆F₄IN₄OSi₂ [M+H]⁺ 597.1, found 597.1.

Synthesis of A-38

A mixture of 1,10-phenanthroline, trifluoromethyl copper (167.78 mg,0.54 mmol) and[3-fluoro-5-(3-iodo-7-trimethylsilyl-triazolo[1,5-a]pyridin-5-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-4-pyridyl]-trimethyl-silane(320 mg, 0.54 mmol) in DMF (3.58 mL) was stirred at 45° C. for 24 hoursin 20 m L sealed tube under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL×2) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(PE/EtOAc=5/1) to give the product (130 mg, 0.24 mmol, 45% yield,) as anoil, which was used directly without any further purification.

Synthesis of 31

To a mixture of[3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-[3-(trifluoromethyl)-7-trimethylsilyl-triazolo[1,5-a]pyridin-5-yl]-4-pyridyl]-trimethyl-silane(130 mg, 0.24 mmol) in THF (20 mL) was added TBAF (1.21 mL, 1.21 mmol),then the mixture was stirred at 20° C. for 1 hour. The mixture wasdiluted with H₂O (20 mL), and the mixture was extracted with EtOAc (30mL×2). The combined organic phase was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=4:1) to give the impure product. The impure product waspurified by Prep-HPLC [Boston Prime C18 (150 mm×30 mm, 5 μm) A=H₂O(0.05% NH₄OH) and B=CH₃CN; 64-94% B over 8 minutes] to give the product(2.84 mg, 7.1 μmol, 3% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.90 (d, 1H), 8.27 (d, 1H), 7.94 (s, 1H), 7.72 (dd, 1H), 7.32 (dd,1H), 5.97-5.85 (m, 1H), 1.60 (d, 3H). LCMS R_(t)=2.10 min in 3.0 minchromatography, 30-90CD, purity 100%, MS ESI calcd. for C₁₅H₁₀F₇N₄O[M+H]⁺ 395.1, found 395.0.

Example 32 Synthesis of Compound 32

To a mixture of methyl 4-chloropyridine-2-carboxylate (10 g, 58.28 mmol)and CaCl₂ (25.87 g, 233.13 mmol) in Methanol (100 mL) and THF (50 mL)was added NaBD₄ (6.1 g, 145.7 mmol) at 0° C., then the mixture wasstirred at 20° C. for 16 hours. The mixture was quenched with sat. NH₄Cl(50 mL), the mixture was extracted with EtOAc (100 mL×3). The combinedorganic phase was washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 35% to70%) to give the product (6500 mg, 44.394 mmol) as oil. ¹H NMR (400 MHz,DMSO-d₆) 400 MHz δ_(H)=8.45 (d, 1H), 7.50 (d, 1H), 7.39 (dd, 1H),5.60-5.47 (m, 1H). LCMS R_(t)=0.13 min in 1.5 min chromatography,5-95AB, purity 99.43%, MS ESI calcd. for C₆H₅D₂ClNO [M+H]⁺ 146.0, found145.8.

To a mixture of (4-chloro-2-pyridyl)-dideuterio-methanol (6.5 g, 44.65mmol) in Chloroform (150 mL) was added MnO₂ (58.23 g, 669.73 mmol), thenthe mixture was stirred at 70° C. for 2 hours. The mixture was filteredthrough Celite, eluted with CHCl₃ (100 mL×2), the filtrate wasconcentrated give the product (3700 mg, 25.95 mmol) as a solid. ¹H NMR(400MHZ, DMSO-d₆) δ_(H)=8.80 (d, 1H), 7.97 (d, 1H), 7.87 (dd, 1H).

A mixture of (4-chloro-2-pyridyl)-deuterio-methanone (3.65 g, 25.6 mmol)and 4-methylbenzenesulfonohydrazide (4.77 g, 25.6 mmol) in Ethanol (30mL) was stirred at 20° C. for 1 hour. The solid was collected byfiltration, then washed with EtOH (5 mL), dried in oven to give theproduct (6700 mg, 20.89 mmol) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=11.97 (s, 1H), 8.53 (d, 1H), 7.78 (d, 2H), 7.71 (d, 1H), 7.54 (dd,1H), 7.43 (d, 2H), 2.37 (s, 3H). LCMS R_(t)=0.77 min in 1.5 minchromatography, 5-95AB, purity 96.89%, MS ESI calcd. for C₁₃H₁₂DClN₃O₂S[M+H]⁺ 311.0, found 311.0.

A mixture ofN-[[(4-chloro-2-pyridyl)-deuterio-methylene]amino]-4-methyl-benzenesulfonamide(1 g, 3.22 mmol) and morpholine (0.56 mL, 6.44 mmol) in Toluene (40 mL)was stirred at 80° C. for 2 hours. After cooling to room temperature,the mixture was washed with water (20 mL×2) and brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 40% to 70%) to give the product (460 mg, 2.94 mmol) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.68 (dd, 1H), 7.74 (dd, 1H),6.96 (dd, 1H). LCMS R_(t)=0.66 min in 1.5 min chromatography, 5-95AB,purity 98.86%, MS ESI calcd. for C₆H₄DClN₃ [M+H]⁺ 155.0, found 154.8.

A mixture of 5-chloro-3-deuterio-triazolo[1,5-a]pyridine (80 mg, 0.51mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(232.26 mg, 0.56 mmol), Pd(t-Bu₃P)₂ (39.22 mg, 80.0 μmol) and K₃PO₄(217.24 mg, 1.02 mmol) in 1,4-Dioxane (5 mL) and D₂O (1 mL) was stirredat 80° C. for 2 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (71.64 mg, 217.1 μmol) asa solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.20 (dd, 1H), 8.57 (d, 1H),8.47-8.33 (m, 2H), 7.61 (dd, 1H), 6.09-5.95 (m, 1H), 1.54 (d, 3H). LCMSR_(t)=1.25 min in 2.0 min chromatography, 10-80AB, purity 99.49%, MS ESIcalcd. for C₁₄H₁₀DF₄N₄O [M+H]⁺ 328.1, found 327.9. ESI calcd. forC₁₄H₁₀DF₄N₄O [M+H]⁺ 328.0926, found 328.0882.

Example 33 Synthesis of Compound 33

A mixture of 5-chloro-3-deuterio-triazolo[1,5-a]pyridine (80 mg, 0.51mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(188.59 mg, 0.56 mmol), Pd(t-Bu₃P)₂ (39.22 mg, 80.0 μmol) and K₃PO₄(217.24 mg, 1.02 mmol) in 1,4-Dioxane (5 mL) and D₂O (1 mL) was stirredat 80° C. for 2 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (79.72 mg, 241.5 μmol) asa solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.20 (dd, 1H), 8.57 (d, 1H),8.47-8.33 (m, 2H), 7.61 (dd, 1H), 6.09-5.95 (m, 1H), 1.54 (d, 3H). LCMSR_(t)=1.24 min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₄H₁₀DF₄N₄O [M+H]⁺ 328.1, found 327.9. MS ESI calcd. forC₁₄H₁₀DF₄N₄O [M+H]⁺ 328.0926, found 328.0881.

Example 34 Synthesis of Compound 34

A mixture of 5-chloro-3-deuterio-triazolo[1,5-a]pyridine (70 mg, 0.45mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(158.11 mg, 0.49 mmol), Pd(t-Bu₃P)₂ (34.32 mg, 0.07 mmol) and K₃PO₄(190.08 mg, 0.90 mmol) in 1,4-Dioxane (5 mL) and D₂O (0.88 mL, 43.68mmol) was stirred at 80° C. for 2 hours under N₂. After cooling to roomtemperature, the mixture was filtered through Celite, and eluted withEtOAc (10 mL×2), and the filtrate was concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (Waters Xbridge 150mm×25 mm 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 40-60% B over 7minutes) to give the product (74.05 mg, 0.24 mmol) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=9.20 (d, 1H), 8.59 (d, 1H), 8.44-8.36 (m, 2H),7.62 (dd, 1H), 5.17 (q, 2H). LCMS R_(t)=1.17 min in 2.0 minchromatography, 10-80AB, purity 100%, MS ESI calcd. for C₁₃H₈DF₄N₄O[M+H]⁺ 314.1, found 313.9.

Example 35 Synthesis of Compound 35

A mixture of 5-chloro-3-deuterio-triazolo[1,5-a]pyridine (70 mg, 0.45mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(171.93 mg, 0.49 mmol), Pd(t-Bu₃P)₂ (34.32 mg, 0.07 mmol) and K₃PO₄(190.08 mg, 0.90 mmol) in 1,4-Dioxane (5 mL) and D₂O (0.88 mL, 43.68mmol) was stirred at 80° C. for 2 hours under N₂. After cooling to roomtemperature, the mixture was diluted with H₂O (10 mL), and the mixturewas extracted with EtOAc (20 mL×2). The organic phase was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (Boston PrimeC18 (150×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 53-83% B over 8minutes) to give the product (43.05 mg, 126.1 μmol) as a solid ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=9.19 (d, 1H), 8.60-8.54 (m, 1H), 8.40-8.33 (m,2H), 7.64-7.58 (m, 1H), 1.82 (s, 6H). LCMS R_(t)=1.30 min in 2.0 minchromatography, 10-80AB, purity 99.41%, MS ESI calcd. for C₁₅H₁₂DF₄N₄O[M+H]⁺ 342.1, found 341.9.

Example 36 Synthesis of Compound 36

A mixture of 5-chloro-3-deuterio-triazolo[1,5-a]pyridine (100 mg, 0.65mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine(303.71 mg, 0.84 mmol), Pd(t-Bu₃P)₂ (49.59 mg, 0.10 mmol) and K₃PO₄(274.68 mg, 1.29 mmol) in 1,4-Dioxane (5 mL) and D₂O (1 mL) was stirredat 80° C. for 2 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (33.79 mg, 94.7 μmol) asa solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.18 (d, 1H), 8.56 (d, 1H),8.42-8.32 (m, 2H), 7.61 (dd, 1H), 2.96-2.82 (m, 2H), 2.72-2.61 (m, 2H),2.06-1.79 (m, 2H). LCMS Rt=1.32 min in 2.0 min chromatography, 10-80AB,purity 100%, MS ESI calcd. for C₁₆H₁₂DF₄N₄O [M+H]⁺ 354.1, found 353.9.MS ESI calcd. for C₁₆H₁₂DF₄N₄O [M+H]⁺ 354.1083, found 354.1093.

Example 37 Synthesis of Compound 37

To a mixture of DIPA (6.35 g, 62.71 mmol) in THF (150 mL) was addedn-BuLi (27.59 mL, 68.98 mmol) at −20° C., then the mixture was stirredat −20-0° C. for 2 hours. To the mixture was added4-chloro-2-methyl-pyridine (4 g, 31.36 mmol) at −78° C., after 10minutes, to the mixture was added TMEDA (7.29 g, 62.71 mmol). Then themixture was stirred at −78° C. for 1 hour. To the mixture was addedmethyl carbonochloridate (6.3 g, 66.67 mmol), then the mixture wasstirred at −78° C. to 20° C. for 2 hours. The mixture was quenched withsat. NH₄Cl (100 mL), then the mixture was extracted with EtOAc (100mL×2). The combined organic phase was washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 15% to 30%) to give the product (4300 mg,11.35 mmol) as an oil. LCMS R, =0.58 min in 1.5 min chromatography,5-95AB, purity 49.00%, MS ESI calcd. for C₈H₉ClNO₂ [M+H]⁺ 186.0, found186.0.

To a mixture of methyl 2-(4-chloro-2-pyridyl)acetate (5.2 g, 28.02 mmol)and p-ABSA (7.4 g, 30.82 mmol) in MeCN (130 mL) was added DBU (4.69 g,30.82 mmol) at 0° C., then the mixture was stirred at 20° C. for 16hours. The mixture was quenched with sat. NH₄Cl (100 mL), and themixture was extracted with EtOAc (100 mL×2). The combined organic phasewas washed with water (50 mL×2) and brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to20% to 35%) to give the impure product, which was triturated fromEtOAc/PET (20 mL/20 mL) and dried in an oven to give the product (2720mg, 12.45 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.76 (d, 1H),8.29 (d, 1H), 7.13 (dd, 1H), 4.06 (s, 3H). LCMS R_(t)=0.71 min in 1.5min chromatography, 5-95AB, purity 96.87%, MS ESI calcd. forC₈H₇ClN₃O₂[M+H]⁺ 212.0, found 212.0.

To the mixture of methyl 5-chlorotriazolo[1,5-a]pyridine-3-carboxylate(2.2 g, 10.4 mmol) in THF (150 mL) was added DIBAL-H (26 mL, 26.00 mmol)at 0° C., then the mixture was stirred at 5° C. for 1 hour. To themixture was added saturated solution of potassium sodium tartrate (˜100mL) and EtOAc (100 mL), and the mixture was stirred at 20° C. for 1hour. After separation, the aqueous phase was extracted with EtOAc (100mL). The combined organic phase was washed with brine (50 mL×2), driedover Na₂SO₄, filtered and concentrated to give the product (1800 mg,9.70 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.64 (d, 1H), 7.87(d, 1H), 6.97 (dd, 1H), 5.10 (d, 2H), 2.15 (t, 1H). LCMS R_(t)=0.51 minin 1.5 min chromatography, 5-95AB, purity 98.96%, MS ESI calcd. forC₇H₇ClN₃O [M+H]⁺ 184.0, found 184.0.

To a mixture of (5-chlorotriazolo[1,5-a]pyridin-3-yl)methanol (1.3 g,7.08 mmol) in Chloroform (100 mL) was add MnO₂ (9.23 g, 106.21 mmol),then the mixture was stirred at 70° C. for 2 hours. The mixture wasfiltered through Celite, eluted with CHCl₃ (50 mL×2), the filtrate wasconcentrated to give the crude product (1150 mg, 6.07 mmol, 86% yield,95.90% purity) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=10.34 (s, 1H),8.80 (d, 1H), 8.39 (d, 1H), 7.21 (dd, 1H). LCMS R_(t)=0.64 min in 1.5min chromatography, 5-95AB, purity 95.90%, MS ESI calcd. for C₇H₅ClN₃O[M+H]⁺ 182.0, found 182.0.

To a mixture of 5-chlorotriazolo[1,5-a]pyridine-3-carbaldehyde (500 mg,2.75 mmol) in DCM (30 mL) was added DAST (1.83 mL, 13.77 mmol), then themixture was stirred at 20° C. for 12 hours. The mixture was poured intoice-water (30 mL) and the mixture was basified with NaHCO₃ (solid) topH˜ 9 and extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to10% to 20%) to give the product (500 mg, 2.38 mmol) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ_(H)=9.27 (dd, 1H), 8.24 (d, 1H), 7.71-7.37 (m, 2H).LCMS R_(t)=0.76 min in 1.5 min chromatography, 5-95AB, purity 97.00%, MSESI calcd. for C₇II₅ClF₂N₃[M+H]⁺ 204.0, found 204.0.

A mixture of 5-chloro-3-(difluoromethyl)triazolo[1,5-a]pyridine (70 mg,0.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(138.27 mg, 0.41 mmol), Pd(t-Bu₃P)₂ (26.36 mg, 50.0 mol) and K₃PO₄ (146mg, 0.69 mmol) in 1,4-Dioxane (5 mL) and Water (0.70 mL) was stirred 80°C. for 12 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=5:1) to give the impure product, which was triturated fromi-Pr₂O/Hexane (1 mL/2 mL) to give the product (37.39 mg, 99.2 μmol) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.34 (d, 1H), 8.62 (d, 1H), 8.48(dd, 1H), 8.43 (s, 1H), 7.77 (dd, 1H), 7.57 (t, 1H), 6.11-5.98 (m, 1H),1.54 (d, 3H).

LCMS R_(t)=1.32 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₁₅H₁₁F₆N₄O [M+H]⁺ 377.1, found 376.9.

Example 38 Synthesis of Compound 38

A mixture of 5-chloro-3-(difluoromethyl)triazolo[1,5-a]pyridine (70 mg,0.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (149.79 mg, 0.45 mmol),Pd(t-Bu₃P)₂ (26.36 mg, 50.0 μmol) and K₃PO₄ (146 mg, 0.69 mmol) in1,4-Dioxane (5 mL) and Water (0.70 mL) was stirred 80° C. for 3 hoursunder N₂. After cooling to room temperature, the mixture was dilutedwith H₂O (10 mL), and the mixture was extracted with EtOAc (20 mL×2).The combined organic phase was washed with water (10 mL) and brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=5:1) to give the impure product, which was triturated fromi-Pr₂O/Hexane (2 mL/2 mL) to give the product (50.28 mg, 133.3 μmol) asa solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.34 (d, 1H), 8.62 (d, 1H),8.48 (dd, 1H), 8.43 (s, 1H), 7.77 (dd, 1H), 7.57 (t, 1H), 6.10-5.98 (m,1H), 1.54 (d, 3H). LCMS R_(t)=1.32 min in 2.0 min chromatography,10-80AB, purity 100%, MS ESI calcd. for C₁₅H₁₁F₆N₄O [M+H]⁺ 377.1, found376.9.

Example 39 Synthesis of Compound 39

A mixture of 5-chloro-3-(difluoromethyl)triazolo[1,5-a]pyridine (70 mg,0.34 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(156.06 mg, 0.45 mmol), Pd(t-Bu₃P)₂ (26.36 mg, 50.0 μmol) and K₃PO₄ (146mg, 0.69 mmol) in 1,4-Dioxane (5 mL) and Water (0.70 mL) was stirred 80°C. for 3 hours under N₂. After cooling to room temperature, the mixturewas diluted with H₂O (10 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic phase was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=4:1) to give the impure product, which was triturated fromi-Pr₂O/Hexane (3 mL/1 mL) to give the product (46.99 mg, 119.8 μmol) asa solid. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=9.33 (d, 1H), 8.62 (d, 1H),8.50-8.38 (m, 2H), 7.77 (dd, 1H), 7.57 (t, 1H), 1.83 (s, 6H). LCMSRt=1.35 min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₆H₁₃F₆N₄O [M+H]⁺ 391.1, found 390.9.

Example 40 Synthesis of Compound 40

To a mixture of (5-chlorotriazolo[1,5-a]pyridin-3-yl)methanol (350 mg,1.91 mmol) in DCM (20 mL) was added MsCl (0.26 mL, 3.4 mmol) at 0° C.,to the mixture was added Et₃N (0.36 mL, 2.6 mmol), then the mixture wasstirred at 0° C. for 30 minutes. To the mixture was added CD₃OD (15 mL)then the mixture was stirred at 20° C. for 16 hours. The mixture wasquenched with sat. NH₄Cl (30 mL), then the mixture was extracted withEtOAc (50 mL×2). The combined organic phase was washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 20% to 40%) to give the product (300 mg,1.50 mmol) as oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.63 (d, 1H), 7.83 (d,1H), 6.96 (dd, 1H), 4.88 (s, 2H). LCMS R_(t)=0.66 min in 1.5 minchromatography, 5-95AB, purity 100%, MS ESI calcd. for C₈H₆D3ClN₃O[M+H]⁺ 201.1, found 201.0.

A mixture of5-chloro-3-(trideuteriomethoxymethyl)triazolo[1,5-a]pyridine (100 mg,0.50 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(191.41 mg, 0.55 mmol), Pd(t-Bu₃P)₂ (38.21 mg, 70.0 μmol) and K₃PO₄(211.62 mg, 1 mmol) in 1,4-Dioxane (5 mL) and D₂O (1 mL) was stirred at80° C. for 3 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the impure product, which wastriturated from Hexane (5 mL) to give the product (110 mg, 0.28 mmol))as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.78 (d, 1H), 8.25 (d, 1H),7.94 (s, 1H), 7.68 (dd, 1H), 7.18 (dd, 1H), 4.96 (s, 2H), 1.88 (s, 6H).LCMS R_(t)=1.27 min in 2.0 min chromatography, 10-80AB, purity 98.01%,MS ESI calcd. for C₁₇H₁₄D3F₄N₄O₂ [M+H]⁺ 388.1, found 387.9. MS ESIcalcd. for C₁₇H₁₄D3F₄N₄O₂ [M+H]⁺ 388.1470, found 388.1500.

Example 41 Synthesis of Compound 41

To a mixture of 5-chlorotriazolo[1,5-a]pyridine-3-carbaldehyde (670 mg,3.69 mmol) in THF (15 mL) and Methanol (15 mL) was added NaBD₄ (308.91mg, 7.38 mmol) at 0° C., then the mixture was stirred at 20° C. for 16hours. The mixture was quenched with sat. NH₄Cl (10 mL), then themixture was extracted with EtOAc (20 mL×2). The combined organic phasewas washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product (650 mg, 3.52 mmol, 95% yield) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.63 (d, 1H), 7.87 (d, 1H), 6.96(dd, 1H), 5.08 (s, 1H), 2.29 (br s, 1H).

A mixture of (5-chlorotriazolo[1,5-a]pyridin-3-yl)-deuterio-methanol(650 mg, 3.52 mmol) and MnO₂ (3.67 g, 42.25 mmol) in Chloroform (30 mL)was stirred at 70° C. for 1 hour. After cooling to room temperature, themixture was filtered through Celite, eluted with CHCl₃ (15 mL×2), thefiltrate was concentrated to give the crude product (550 mg, 3.01 mmol,86% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.80 (d, 1H), 8.39(d, 1H), 7.21 (dd, 1H).

To a mixture of (5-chlorotriazolo[1,5-a]pyridin-3-yl)-deuterio-methanone(550 mg, 3.01 mmol) in THF (10 mL) and Methanol (10 mL) was added NaBD₄(252.18 mg, 6.02 mmol) at 0° C., then the mixture was stirred at 20° C.for 16 hours. The mixture was quenched with sat. NH₄Cl (20 mL), then themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with brine (30 mL×2), dried over Na₂SO₄, filtered andconcentrated to give the crude product (400 mg, 2.16 mmol, 72% yield) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.64 (dd, 1H), 7.87 (d, 1H), 6.97(dd, 1H), 2.04 (br s, 1H).

To a mixture of(5-chlorotriazolo[1,5-a]pyridin-3-yl)-dideuterio-methanol (250 mg, 1.35mmol) in DCM (15 mL) was added MsCl (0.17 mL, 2.16 mmol) at 0° C.,followed by Et₃N (0.24 mL, 1.75 mmol), then the mixture was stirred at0° C. for 30 minutes. To the mixture was added Methanol (10 mL) then themixture was stirred at 20° C. for 16 hours. The mixture was quenchedwith sat. NH₄Cl (30 mL), then the mixture was extracted with EtOAc (50mL×2). The combined organic phase was washed with brine (15 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 20% to 40%) to give the product (130 mg, 0.63 mmol,) as anoil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.64 (dd, 1H), 7.83 (dd, 1H), 6.96(dd, 1H), 3.44 (s, 3H). LCMS R_(t)=0.67 min in 1.5 min chromatography,5-95AB, purity 96.12%, MS ESI calcd. for C₈H₇D₂ClN₃O [M+H]⁺ 200.0, found200.0.

A mixture of5-chloro-3-[dideuterio(methoxy)methyl]triazolo[1,5-a]pyridine (120 mg,0.60 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(230.85 mg, 0.66 mmol), Pd(t-Bu₃P)₂ (46.08 mg, 90.0 μmol) and K₃PO₄(255.23 mg, 1.2 mmol) in 1,4-Dioxane (7 mL) and D₂O (1 mL) was stirredat 80° C. for 3 hours under N₂. After cooling to room temperature, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (10mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (92.01 mg, 0.24 mmol) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.78 (d, 1H), 8.25 (d, 1H), 7.93(s, 1H), 7.68 (dd, 1H), 7.18 (dd, 1H), 3.46 (s, 3H), 1.88 (s, 6H). LCMSR_(t)=1.30 min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₁₇H₁₅D2F₄N₄O₂ [M+H]⁺ 387.1, found 387.0. MS ESI calcd. forC₁₇H₁₅D2F₄N₄O₂ [M+H]⁺ 387.1408, found 387.1481.

Example 42. Synthesis of Compound 42

To a mixture of I₂ (50 mg, 0.20 mmol) and Mg (451.64 mg, 18.58 mmol) inEther (5 mL) was added a solution of CD₃I (3 g, 20.7 mmol) in Ether (6mL) dropwise under N₂ over 30 minutes. Then the reaction mixture wasstirred at 20° C. for 1 hour to give a silver gray solution. To themixture 4-bromopyridine-2-carbonitrile (1.7 g, 9.29 mmol) in THF (34 mL)was added the solution of CD₃MgI at 0° C., then the mixture was stirredat 0° C. for 1 hour. The reaction mixture was poured into 1N HCl (50 mL)and ice (30 g), then basified with Na₂CO₃ (solid) to pH˜ 8, the mixturewas extracted with EtOAc (50 mL×2). The combined organic phase waswashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give theproduct (1500 mg, 7.25 mmol, 78% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.50 (d, 1H), 8.20 (d, 1H), 7.65 (dd, 1H). LCMS R_(t)=0.74min in 1.5 min chromatography, 5-95AB, purity 98.13%, MS ESI calcd. forC₇H₄D₃BrNO [M+H]⁺ 203.0, found 202.9.

A mixture 4-methylbenzenesulfonohydrazide (1.51 g, 8.13 mmol) and1-(4-bromo-2-pyridyl)-2,2,2-trideuterio-ethanone (1.5 g, 7.39 mmol) inEthanol (10 mL) was stirred at 20° C. for 2 hours. The solid wascollected by filtered, then was washed with PET (3 mL), dried in oven togive the product (2600 mg, 7.0 mmol, 95% yield) as a solid. ¹H NMR (400MHz, DMSO-d₆) δ_(H)=10.98 (s, 1H), 8.44 (d, 1H), 7.87-7.77 (m, 3H), 7.66(dd, 1H), 7.43 (d, 2H), 2.37 (s, 3H). LCMS R_(t)=0.87 min in 1.5 minchromatography, 5-95AB, purity 100%, MS ESI calcd. for C₁₄H₁₂D3BrN₃O₂S[M+H+2]⁺ 373.0, found 373.1.

A mixture of morpholine (0.7 mL, 8.08 mmol) andN-[[1-(4-bromo-2-pyridyl)-2,2,2-trideuterio-ethylidene]amino]-4-methyl-benzenesulfonamide(600 mg, 1.62 mmol) in Toluene (20 mL) was stirred at 80° C. for 12hours. After cooling to room temperature, the mixture was diluted withEtOAc (30 mL), then washed with 0.5N HCl (20 mL), water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 40% to 70%) to give the product (310 mg,1.43 mmol, 89% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.52(dd, 1H), 7.81 (dd, 1H), 6.99 (dd, 1H). LCMS R_(t)=0.61 min in 1.5 minchromatography, purity 99.52%, MS ESI calcd. for C₇H₄D₃BrN₃ [M+H]⁺215.0, found 214.9.

A mixture of 5-bromo-3-(trideuteriomethyl)triazolo[1,5-a]pyridine (70mg, 0.33 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(125 mg, 0.36 mmol), Pd(t-Bu₃P)₂ (24.95 mg, 50.0 μmol) and K₃PO₄ (138.2mg, 0.65 mmol) in 1,4-Dioxane (8 mL) and D₂O (0.88 mL, 43.68 mmol) wasstirred at 80° C. for 5 hours under N₂. After cooled to roomtemperature, the mixture was diluted with H₂O (20 mL), and the mixturewas extracted with EtOAc (30 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-TLC (silica gel, PE:EtOAc=3:1) to give the product(51.06 mg, 142.9 μmol, 44% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.73 (d, 1H), 8.24 (d, 1H), 7.72 (s, 1H), 7.67 (d, 1H), 7.11 (d,1H), 1.87 (s, 6H). LCMS R_(t)=1.32 min in 2.0 min chromatography,5-95AB, purity 100%, MS ESI calcd. for C₁₆H₁₂D3F₄N₄O [M+H]⁺ 358.1, found358.1. MS MS ESI calcd. for C₁₆H₁₂D3F₄N₄O [M+H]⁺ 358.1365, found358.1383.

Example 43. Synthesis of Compound 43

A mixture of 1-(4-bromo-2-pyridyl)ethanone (2 g, 10 mmol) and4-methylbenzenesulfonohydrazide (2.79 g, 15 mmol) in Ethanol (30 mL) wasstirred at 15° C. for 3 hours to give a mixture. The reaction mixturewas concentrated to give the crude product (3700 mg, 7.34 mmol, 73%yield) as a solid. LCMS R_(t)=0.86 min in 1.5 min chromatography,5-95AB, purity 73.06%, MS ESI calcd. for C₁₄H₁₅BrN₃O₂S [M+H+2]⁺ 470.0,found 370.0.

A mixture ofN-[1-(4-bromo-2-pyridyl)ethylideneamino]-4-methyl-benzenesulfonamide(3.7 g, 10.05 mmol) in morpholine (30 g, 344.35 mmol) was stirred at100° C. for 2 hours. After cooling to room temperature, the reactionmixture was concentrated. The residue was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give theproduct (2100 mg, 9.35 mmol, 93% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.51 (dd, 1H), 7.81 (d, 1H), 6.99 (dd, 1H), 2.59 (s, 3H).LCMS Rt=0.70 min in 1.5 min chromatography, 5-95AB, purity 94.46%, MSESI calcd. for C₇H₇BrN₃ [M+H]⁺ 212.0, found 211.7.

A mixture of 5-bromo-3-methyl-triazolo[1,5-a]pyridine (100 mg, 0.47mmol), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (133.53 mg,0.57 mmol), Pd(t-Bu₃P)₂ (36.15 mg, 0.07 mmol), and K₃PO₄ (200.24 mg,0.94 mmol) in 1,4-Dioxane (6 mL) and Water (1 mL) was stirred at 85° C.for 16 hours. After cooling to room temperature, the suspension wasdiluted with EtOAc (10 mL), filtered through silica gel, eluted withEtOAc (20 mL). The combined filtrates were concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 50%) to give the product (142.76mg, 0.44 mmol, 94% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.64(d, 1H), 7.67 (s, 1H), 7.40 (d, 1H), 7.13 (dd, 1H), 6.96 (dd, 1H), 6.87(s, 1H), 3.88 (s, 3H), 2.65 (s, 3H). LCMS R_(t)=1.28 min in 2 minchromatography, 10-80AB, purity 100%, MS ESI calcd. forC₁₅H₁₃F₃N₃O₂[M+H]⁺ 324.1, found 423.9.

Example 44. Synthesis of Compound 44

A mixture of3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(285.91 mg, 0.85 mmol), 5-chloro-7-methyl-triazolo[1,5-a]pyridine (130mg, 0.78 mmol), Pd(t-Bu₃P)₂ (59.46 mg, 0.12 mmol) and K₃PO₄ (329.34 mg,1.55 mmol) in 1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 80° C.for 16 hours under N₂. After cooling to room temperature, the mixturewas filtered through Celite and eluted with EtOAc (20 mL×2), and thefiltrate was concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to30%) to give the impure product. The impure product was triturated fromn-hexane/CH₂Cl₂ (2:1, 3 ml) to give the product 10.28 mg, 29.6 μmol, 4%yield) as a solid. ¹H NMR (400 MHz, CDCl₃+D₂O) δ_(H)=8.24-8.21 (m, 1H),8.18 (s, 1H), 7.75 (s, 1H), 7.68 (dd, 1H), 6.98 (s, 1H), 5.94-5.84 (m,1H), 2.99 (s, 3H), 1.59 (d, 3H). LCMS R_(t)=1.26 min in 2.0 minchromatography, 10-80AB, purity, 100%, MS ESI calcd. for C₁₅H₁₃F₄N₄O[M+H]⁺ 341.1, found 340.9.

Example 45. Synthesis of Compound 45

A mixture of 5-chloro-7-methyl-triazolo[1,5-a]pyridine (150 mg, 0.89mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (359.89 mg, 1.07 mmol),K₃PO₄ (379.96 mg, 1.79 mmol), Pd(t-Bu₃P)₂ (68.61 mg, 0.13 mmol) in1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80° C. for 12hours. After cooling to room temperature, the reaction mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (15 mL×2).The combined organic phase was washed with water (30 mL), brine (30 mL),dried over Na₂SO₄ and concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Boston Prime C18 (150×30 mm, 5 um),A=H₂O (0.05% NH₄OH) and B=CH₃CN; 54-74% B over 9 minutes) to give theproduct (8.4 mg, 24.7 μmol, 3% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.22 (d, 1H), 8.18 (s, 1H), 7.75 (s, 1H), 7.68 (dd, 1H),6.98 (s, 1H), 5.95-53.84 (m, 1H), 2.99 (s, 3H), 1.60 (s, 3H). LCMSR_(t)=1.29 min in 2.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. C₁₅H₁₃F₄N₄O [M+H]⁺ 341.09, found 341.0.

Example 46. Synthesis of Compound 46

To a solution of 5-chlorotriazolo[1,5-a]pyridine (500 mg, 3.26 mmol) inTHF (30 mL) was added LDA (2.44 mL, 4.88 mmol) at −70° C. After theaddition, the solution was stirred at −70° C. for 1 hours. To themixture was added CH₃I (1.57 mL, 25.15 mmol) at −70° C., and the mixturewas stirred at −70° C. for 1 hour. The mixture was quenched with sat.NH₄Cl (50 mL), then the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to20% to 40%) to give the product (470 mg, 2.80 mmol, 86% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.08-8.03 (m, 1H), 7.64 (d, 1H),6.79 (d, 1H), 2.90 (s, 3H).

A mixture of 5-chloro-7-methyl-triazolo[1,5-a]pyridine (150 mg, 0.89mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(344.84 mg, 1.07 mmol), K₃PO₄ (379.96 mg, 1.79 mmol), Pd(t-Bu₃P)₂ (68.61mg, 0.13 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at80° C. for 12 hours. After cooling to room temperature, the reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(15 mL×2). The combined organic phase was washed with water (30 mL),brine (30 mL), dried over Na₂SO₄ and concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (Boston Prime C18(150 mm×30 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 60-80% B over 9minutes) to give the product (14.72 mg, 44.4 μmol, 5% yield) as a solid.¹H NMR (400 MHz, CDCl₃) δ_(H)=8.23 (d, 1H), 8.19 (s, 1H), 7.76 (d, 1H),7.70 (dd, 1H), 6.98 (d, 1H), 4.92 (q, 2H), 2.99 (s, 3H). LCMS R_(t)=1.22min in 2.0 min chromatography, 10-80AB, purity 99.23%, MS ESI calcd.C₁₄H₁₁F₄N₄O [M+H]⁺ 327.08, found 326.9.

Example 47. Efficacy of Exemplary Compounds in the Modulation of LateSodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaLexpressed by the Navy 1.6 voltage-gated sodium channel was accomplishedusing the PatchXpress™ high throughput electrophysiology platform(Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressingrecombinant, human Na_(V) 1.6 (hNa_(V) 1.6) were grown inDMEM/high-glucose Dulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10mM HEPES and 400 μg/mL G418. Cells were grown to 50%-80% confluencyprior to harvesting. Trypsinized cells were washed, allowed to recoverfor 1 hour and then resuspended in extracellular recording solution at aconcentration of 1×10⁶ cells/mi. The onboard liquid handling facility ofthe PatchXpress was used for dispensing cells and applying testcompounds. Nay late currents were evoked by the application of 300 nMATX-II. INaL was evoked by depolarizing pulses to 0 mV for 200 ms from anon-inactivating holding potential (e.g., −120 mV) at a frequency of 0.1Hz. INaL amplitude and stability were determined by analyzing the meancurrent amplitude over the final 20 ms of the test pulse. Followingsteady state block with exemplary compounds (e.g., as described herein),a Na⁺ free solution containing an impermeant cation (e.g., Choline orNDMG) was added to confirm the identify of the sodium current. Percentsteady-state inhibition of INaL was calculated as:[(INaL_compound)/(INaL_control)]*100, where INaL_compound andINaL_control represent INaL recorded in the presence or absence ofcompound, respectively.

Results from this assay relating to percent inhibition of INaL athNaV1.6 (measured using a procedure similar to described above but usingHEK-293 cells expressing recombinant, human Nay 1.6 (h Nay 1.6) at 1 μMare summarized in Table 1 below. In this table, “A” indicates inhibitionof less than 30%; “B” indicates inhibition of between about 30% to about70%; and “C” indicates inhibition of greater than 70%.

TABLE 1 INaL v1.6 Compound (1 μM, % Inhibition)  1 B  2 C  3 C  4 C  5 C 6 B  7 C  8 B  9 C 10 B 11 C 12 C 13 C 14 B 15 C 16 B 17 C 18 C 19 B 20B 21 C 22 C 23-1 B 23-2 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 32 C33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 C 42 C 43 C 44 B 45 C 46 B

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A method of treating a neurological disorder or a psychiatricdisorder, wherein the method comprises administering to a subject inneed thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; A is aryl or heteroaryl (e.g.,6-membered aryl or heteroaryl), wherein aryl and heteroaryl aresubstituted by one or more R³; R′ is hydrogen, alkyl, —OR^(c), orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R³ is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently, alkyl, deuterium,carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl,and heterocyclyl is optionally substituted by one or more R⁷; each R^(c)is independently hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl, wherein each alkyl is optionallysubstituted by one or more R⁶; each R⁶ is independently alkyl,deuterium, haloalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; and each R⁷ is independently alkyl, halo, or oxo.
 2. The method ofclaim 1, wherein the neurological disorder is epilepsy.
 3. The method ofclaim 1, wherein the neurological disorder is an epilepticencephalopathy.
 4. The method of claim 3, wherein the epilepticencephalopathy comprises Dravet syndrome, infantile spasms, orLennox-Gastaut syndrome.
 5. The method of any one of the precedingclaims, wherein each of X, Y, and Z is independently CR′ (e.g., CH). 6.The method of any one of the preceding claims, wherein A is aryl (e.g.,phenyl).
 7. The method of any one of the preceding claims, wherein A isphenyl substituted by R³.
 8. The method of any one of the precedingclaims, wherein R³ is alkyl or —OR^(c).
 9. The method of any one of thepreceding claims, wherein R³ is alkyl optionally substituted with R⁵(e.g., —CH₃ or —CH₂OCH₃).
 10. The method of any one of the precedingclaims, wherein R³ is —OR^(c).
 11. The method of claim 10, wherein R^(c)is alkyl optionally substituted with R⁶.
 12. The method of claim 11,wherein R³ is —OCF₃.
 13. The method of any one of the preceding claims,wherein R¹ is hydrogen or alkyl.
 14. The method of any one of thepreceding claims wherein R¹ is hydrogen.
 15. The method of any one ofclaims 1-13, wherein R¹ is C₁₋₆ alkyl (e.g., —CH₃).
 16. The method ofclaim 15, wherein R¹ is C₁₋₄ alkyl substituted independently with 1-3 R⁴(e.g., —CF₃).
 17. The method of any one of the preceding claims, whereinthe compound of Formula (I) is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; R′ is hydrogen, alkyl, —OR^(c), orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently, alkyl, carbocyclyl,heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, andheterocyclyl is optionally substituted by one or more R⁷; n is 0, 1, or2; each R^(c) is independently hydrogen, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶; each R^(d) is independently hydrogen or alkyl, wherein eachalkyl is optionally substituted by one or more R⁶; each R⁶ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; and each R⁷ is independently alkyl, halo, or oxo.
 18. The method ofany one of claims 1-16, wherein the compound of Formula (I) is acompound of Formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein: A is aryl orheteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl andheteroaryl are substituted by one or more R³, R¹ is hydrogen, deuterium,alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independently,alkyl, deuterium, carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, and heterocyclyl is optionally substituted by one ormore R⁷; each R^(c) is independently hydrogen, deuterium, alkyl, aryl,or heteroaryl, wherein alkyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH; and each R⁷ is independentlyalkyl, halo, or oxo.
 19. The method of any one of the preceding claims,wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 20. A compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; A is aryl or heteroaryl (e.g.,6-membered aryl or heteroaryl), wherein aryl and heteroaryl aresubstituted by one or more R³; R′ is hydrogen, alkyl, —OR^(c) orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R³ is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently, alkyl, deuterium,carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl,and heterocyclyl is optionally substituted by one or more R⁷; each R^(c)is independently hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl, wherein each alkyl is optionallysubstituted by one or more R⁶; each R⁶ is independently alkyl,deuterium, haloalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; and each R⁷ is independently alkyl, halo, or oxo.
 21. The compoundof claim 20, wherein each of X, Y, and Z is independently CR′ (e.g.,CH).
 22. The compound of any one of claims 20-21, wherein A is aryl(e.g., phenyl).
 23. The compound of any one of claims 20-22, wherein Ais phenyl substituted by R³.
 24. The compound of any one of claims20-23, wherein R³ is alkyl or —OR^(c).
 25. The compound of any one ofclaims 20-24, wherein R³ is alkyl optionally substituted with R⁵ (e.g.,—CH₃ or —CH₂OCH₃).
 26. The compound of any one of claims 20-25, whereinR³ is —OR^(c).
 27. The compound of claim 26, wherein R^(c) is alkyloptionally substituted with R⁶.
 28. The compound of claim 27, wherein R³is —OCF₃.
 29. The compound of any one of claims 20-28, wherein R¹ ishydrogen, deuterium, or alkyl.
 30. The compound of any one of claims20-29, wherein R¹ is hydrogen.
 31. The compound of any one of claims20-29, wherein R¹ is C₁₋₆ alkyl (e.g., —CH₃).
 32. The compound of claim31, wherein R¹ is C₁₋₄ alkyl substituted with 1-3 R⁴ (e.g., —CF₃). 33.The compound of any one of claims 20-32, wherein the compound of Formula(I) is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; R is hydrogen, alkyl, —OR^(c), orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; n is 0, 1, or 2; each of R⁴ and R⁵ is independently, alkyl,carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl,and heterocyclyl is optionally substituted by one or more R⁷; each R^(c)is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl, wherein each alkyl is optionallysubstituted by one or more R⁶; each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R⁷ isindependently alkyl, halo, or oxo.
 34. The compound of any one of claims20-32, wherein the compound of Formula (I) is a compound of Formula(I-b):

or a pharmaceutically acceptable salt thereof, wherein: A is aryl orheteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl andheteroaryl are substituted by one or more R³; R¹ is hydrogen, deuterium,alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independently,alkyl, deuterium, carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, and heterocyclyl is optionally substituted by one ormore R⁷; each R^(c) is independently hydrogen, deuterium, alkyl, aryl,or heteroaryl, wherein alkyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;each R⁶ is independently alkyl, deuterium, haloalkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH; and each R⁷ is independentlyalkyl, halo, or oxo.
 35. The compound of any one of claims 20-32,wherein the compound of Formula (I) is a compound of Formula (I-c):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; R′ is hydrogen, alkyl, —OR^(c), orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; n is 0, 1, or 2; R^(3b) is alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁵; each of R⁴ and R⁵ is independently, alkyl,deuterium, carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c),—N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl,carbocyclyl, and heterocyclyl is optionally substituted by one or moreR⁷; each R^(c) is independently hydrogen, deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶; each R^(d) is independently hydrogen or alkyl, wherein eachalkyl is optionally substituted by one or more R⁶; each R⁶ isindependently alkyl, deuterium, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH; and each R⁷ is independently alkyl, halo, or oxo.
 36. Thecompound of any one of claims 20-32, wherein the compound of Formula (I)is a compound of Formula (I-d):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; R′ is hydrogen, alkyl, —OR^(c), orhalogen; R¹ is hydrogen, deuterium, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; m is 1, 2, or 3; each of R⁴ and R⁵ is independently, alkyl,carbocyclyl, heterocyclyl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl,and heterocyclyl is optionally substituted by one or more R⁷; each R^(c)is independently hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl, wherein each alkyl is optionallysubstituted by one or more R⁶; each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R⁷ isindependently alkyl, halo, or oxo.
 37. The compound of claim 35 or 36,wherein X, Y and Z are CR′.
 38. The compound of claim 35 or 36, whereinX is N, Y and Z are CR′.
 39. The compound of claim 35 or 36, wherein Yis N, X and Z are CR′.
 40. The compound of claim 35 or 36, wherein Z isN, X and Y are CR′.
 41. The compound of any one of claims 35-40, whereinR′ is hydrogen.
 42. The compound of any one of claims 35-41, wherein R′is methyl.
 43. The compound of any one of claims 35-42, wherein R¹ ishydrogen, deuterium, or alkyl, wherein the alkyl is optionallysubstituted with one or more (e.g., 1, 2, or 3) R⁴.
 44. The compound ofany one of claims 35-43, wherein each R^(3a) is independently, alkyl,carbocyclyl, halo, or —OR^(c), wherein the alkyl and carbocyclyl areoptionally substituted with one or more R⁵.
 45. The compound of any oneof claims 35-44, wherein n is 0 or
 1. 46. The compound of any one ofclaims 35-44, wherein m is 1 or
 2. 47. The compound of any one of claims35-46, wherein R^(3b) is alkyl or carbocyclyl, wherein alkyl andcarbocyclyl are optionally substituted with one or more R⁵.
 48. Thecompound of any one of claims 35-47, wherein each of R⁴ is independentlyhalo or —OR^(c).
 49. The compound of any one of claims 35-48, whereineach of R⁵ is independently, alkyl, halo, cyano, or —OR^(c), whereinalkyl is optionally substituted by one or more R⁷.
 50. The compound ofany one of claims 35-49, wherein each R^(c) is independently alkyl,wherein alkyl is optionally substituted by one or more R⁶.
 51. Thecompound of any one of claims each R⁶ is independently halo.
 52. Thecompound of any one of claims 35-51, wherein each R⁷ is independentlyhalo.
 53. The compound of any one of claims 20-52, wherein the compoundis selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 54. A pharmaceuticalcomposition comprising a compound of any one of claims 20-53, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 55. The method of any one of claims 1-19, whereinthe method comprises administering the pharmaceutical composition ofclaim
 54. 56. A method of treating a neurological disorder or apsychiatric disorder, wherein the method comprises administering to asubject in need thereof a compound of any one of claims 20-53, or apharmaceutically acceptable salt thereof or a pharmaceutical compositionof claim 54.